ES2229272T3 - DERIVATIVES OF CONDENSED POLYCLYTIC HETEROCYCLES. - Google Patents

Abstract

NEW FUSIONED POLYCLYTIC HETEROCICLIC DERIVATIVES THAT HAVE EXCELLENT ANTITUMOR EFFECTS AND A PROCESS FOR THEIR PRODUCTION. A COMPOSITE REPRESENTED BY THE FOLLOWING GENERAL FORMULA (I) OR PHARMACOLOGICALLY ACCEPTABLE SALTS OF THE SAME: IN WHICH THE RING REPRESENTS AN OPTIONALLY REPLACED AROMATIC RING OR A FUSIONED BICYCLE RING IN WHICH THE ONE IS RING THROUGH ; RING B REPRESENTS PIRROL, 4H THIAZINE OR 4 (1H) FUSIONATED MONOCICLIC OR BICYCLIC FUSIONED ROMATIC OPTIONALLY REPLACED; EY REPRESENTS A GROUP REPRESENTED BY THE FORMULA -EF (IN WHICH E REPRESENTS A LOWER RENT; YF REPRESENTS AMIDINO, GUANIDINO OR AMINO OPTIONALLY REPLACED WITH AN OPTIONALLY HYDROXYLATED OR OPTIONALLY RENT RENTAL SINGLE BATTERIES IN WHICH THE BATTERIES ARE BATCHED OPTIONALLY SUBSTITUTED, WHICH PRESENT EXCELLENT ANTITUMORAL ACTIVITY.

Description

Derivatives of polycyclic heterocycles condensed

Technical field

This invention relates to derivatives of condensed polycyclic heterocycles, to a procedure for produce the same and to medicinal compositions containing the themselves as active ingredient.

Fundamental technique

\uelm{C}{\para}

O--- en su molécula. Sin embargo, se ha informado de que la amonafida mostraba una fuerte toxicidad de la médula ósea y escasa eficacia en ensayos clínicos realizados hasta ahora [Drugs Fut., 17, 832 (1992)]. Como compuesto tricíclico, se ha informado de la azonafida [2-[2'-(dimetilamino)etil]-1,2-dihidro-3H-dibenz(deh)-isoquinolina-1,3-diona], obtenida convirtiendo el resto aminonaftaleno de la amonafida en antraceno, para aumentar por ello la actividad antitumores en ensayos preclínicos (documento WO9200281).A tricyclic compound amonaphide [5-amino-2- [2- (dimethylamino) ethyl] -1H-benz [de] isoquinoline-1,3 (2H) -dione] is the most famous polycyclic fused heterocyclic antitumor compound, which has a cyclic imido residue
---WITH---

 \ uelm {C} {\ para} 

Or --- in your molecule. However, it has been reported that amonafide showed strong bone marrow toxicity and poor efficacy in clinical trials conducted so far [Drugs Fut., 17, 832 (1992)]. As a tricyclic compound, azonaphide [2- [2 '- (dimethylamino) ethyl] -1,2-dihydro-3H-dibenz (deh) -isoquinoline-1,3-dione], obtained by converting the aminonaphthalene moiety, has been reported of amraphide in anthracene, to increase antitumor activity in preclinical trials (WO9200281).

As heterocyclic anti-tumor substances condensed tetracyclics having a uracil structure in the that a nitrogen atom has been introduced into an imido moiety cyclic, have been known 2- [2- (dimethylamino) ethyl] pyrimid [5,6,1-de] acridine-1,3,7-trione [Pharmaco, 47, 1035 (1992) and 2,3-dihydro-2- [2- (dimethylamino) ethyl] -1H, 7H-naphthylidino [3,2,1-ij] quinazoline-1,3,7 (2H) -trione (J. Med. Chem., 37, 593 (1994)]. However, each of these compounds showed only weak anti-tumor activity in trials preclinical No anti-tumor substances have been reported condensed or pentacyclic or hexacyclic heterocycles of this kind.

The present invention is intended to provide new compounds or new derivatives of pentacyclic heterocycles and condensed hexacyclics that have low toxicity and excellent anti-tumor activity The present invention also seeks provide a process to produce these compounds and medicinal compositions containing these compounds as active ingredient.

Description of the invention

To get the objects mentioned before, the present inventors have conducted extensive studies in order to Develop excellent anti-tumor substances. As a result, they have successfully found that new heterocycle compounds condensed pentacyclics and hexacyclics, which have a structure uracil in the molecule, have excellent anti-tumor activity and low toxicity, thus completing the present invention.

That is, the present invention relates to a compound represented by the following general formula (I) or salts thereof pharmacologically acceptable:

one

in the that

ring A represents an aromatic ring optionally substituted monocyclic or a condensed ring bicyclic in which at least one of the rings is a ring aromatic;

ring B represents pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone;

ring C represents an aromatic ring monocyclic or bicyclic condensate, optionally substituted; and

And represents a represented group or formula -e-f (in which e represents an alkylene C1-C6 and f represents amidino, guanidino or amino optionally substituted with C1-C6 alkyl optionally hydroxylated or optionally alkyl C1-C6aminated;

on the condition that cases in which rings A and C are both monocyclic aromatic rings optionally substituted,

in which optionally substituted in the case of ring A means 1 to 3 substituents selected from the group consisting of hydroxy, oxo, cyano, halogen, nitro optionally hydroxylated or C1-C6 alkyl optionally C1-C6 alkyl, alkoxy C1-C6, acyl C1-C6, carbamoyl optionally C1-C6 alkylated and amino optionally C1-C6 alkylated, C1-C6 acylated, arylsulfonylated or C1-C6 alkyl sulfonylated, and in the which optionally substituted in the case of ring C means 1 to 3 substituents selected from the groups consisting of include halogen, hydroxy, C1-C6 alkyl, alkoxy C1-C6, nitro and C1-C6 amino alkylated or C1-C6 acylated.

In addition, the present invention relates to a medical composition comprising a polycyclic heterocycle condensate as derivative described above in an effective dose pharmacologically or pharmacologically acceptable salts thereof and pharmacologically acceptable excipients.

In addition, the present invention relates to the use of a condensed polycyclic heterocycle derivative as has been described above in a pharmacologically effective dose for manufacture of a medicinal composition to prevent or treat tumors

In the definition of ring A in the formula previous general (I), the expression "aromatic ring monocyclic "means an aromatic 5- or 6-membered ring that optionally contains at least one oxygen or sulfur atom. The expression "bicyclic condensed ring in which at least one of the rings is an aromatic ring "means a ring bicyclic condensate in which each of the rings is a ring 5 to 8 members optionally containing at least one atom of nitrogen, oxygen or sulfur and at least one of the rings is a aromatic ring You can have one to three substituents in the rings

Examples of ring A include benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrole, thiazole and the following bicyclic condensed rings that may be partially hydrogenated and oxidized in a sulfur atom, If it is contained in them. These rings may be condensed to ring B in any arbitrary allowable position chemically

2

3

4

Each of the previous rings can have 1 to 3 substituents. When you have two or more substituents, these Substituents may be the same or different. The examples of Substituents include hydroxy, oxo, cyano, halogen, nitro optionally hydroxylated or lower alkyl alkyl lower-aminated, lower alkoxy, lower acyl, optionally lower alkylated carbamoyl and optionally amino lower alkylated, lower acylated, arylsulfonylated or alkyl lower sulphonylated.

The expression "condensed aromatic ring monocyclic or bicyclic "as used in the definition of the ring C means a monocyclic or bicyclic aromatic hydrocarbon or a aromatic hetero ring containing one or two nitrogen atoms. You can have one to three substituents in the ring (s)

Examples of the C ring include benzene, pyridine, pyrimidine, naphthalene, quinoline, isoquinoline, indole and quinazoline These rings may be condensed to ring B in an arbitrary position chemically permissible.

The rings mentioned above can have each one of 1 to 3 substituents. When they have two or more substituents, These substituents may be the same or different. The examples of Substituents include halogen, hydroxy, lower alkyl, lower alkoxy, nitro and amino optionally lower alkylated or lower acylate

The expression "lower alkyl group" according to it is used in the definition of the substituents of rings A and C in the definition of Y in the previous general formula (I) means a C1-6 linear or branched alkyl group. The examples  thereof include methyl, ethyl, n-propyl groups, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,  1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl Y 1-ethyl-2-methylpropyl. Among these groups, methyl groups may be cited as preferable, ethyl, n-propyl and isopropyl and the most desirable among all are methyl and ethyl groups.

The expression "lower alkylene" as used in the definition of e in Y means a residue obtained removing a hydrogen atom from the lower alkyl group as You have defined before. When an amino group is substituted with two lower alkyl groups in the definition of substituents optionally carried by rings A and C and f at Y, these groups alkyl can be linked together to form a ring of 5 or 6 members.

The lower alkoxy group in the definition of substituents optionally carried by rings A and C means derivatives of the lower alkyl groups mentioned before such as methoxy, ethoxy, n-propoxy groups, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Among these lower alkoxy groups, they can be cited as the most desirable methoxy and ethoxy groups. They are examples of the halogen atom fluorine, chlorine and bromine atoms.

Examples of the lower acyl group include those with 1 to 6 carbon atoms such as formyl groups, acetyl, propionyl, butyryl, isobutyryl and valeryl.

The expression "amino arylsulfonylated or alkyl lower-sulfonylated "as used in the definition of the substituent optionally carried by ring A means, for example, an amino group optionally p-toluenesulfonylated, methylsulfonylated or ethylsulfonylated.

Derivatives of polycyclic heterocycles condensates represented by the above general formula (I) form Sometimes salts with acids. The salts of the compounds (I) also are included in the scope of the present invention. The Examples of acid salts include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, etc. and you leave organic acids such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, methanesulfonate, p-toluenesulfonate, etc.

Needless to say, the present invention also involves hydrates of these compounds and optical isomers thereof, if any. Although the compounds of the present invention have an effective anti-tumor activity, compounds that exhibit anti-tumor activity when metabolized, for example, are oxidized, reduced, hydrolyzed or conjugated in vivo, are also involved . Furthermore, the present invention involves compounds capable of forming the compounds of the present invention when metabolized, for example, oxidized, reduced or hydrolyzed in vivo .

The compounds (I) of the present invention They can be produced by various procedures. Will be described now Typical examples of these production procedures.

1) A compound of general formula (I) can occur by reacting a compound represented by the following general formula (II):

5

in which the rings Aa and Ca respectively represent rings A and C optionally protected; the Ba ring represents 4H-1,4-oxazine, 4H-1,4-thiazine, 4 (1H) -pyridone or pyrrole; fa means f optionally protected; and e has the same meaning as the definite before,

with a compound represented by the following general formula (III):

\delm{C}{\delm{\dpara}{O}}

---E(III) D ---

 \ delm {C} {\ delm {\ dpara} {O}} 

---AND

in which D and E are equal or different and each represents a group labile.

This reaction is usually carried out. dissolving compound (II) in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dioxane, adding thereto 2 to 3 equivalents of sodium hydride and then adding the compound (III).

Examples of compound (III) include phosgene, ethyl chlorocarbonate and N, N'-carbonyldiimidazole. This reaction is performed. usually in a temperature range of -50 to 150 ° C.

When the product obtained in this way is protected in the amino or hydroxyl group, etc., can be unlocked by a method conventional such as a treatment with an acid or an alkali or catalytic reduction to thereby give the intended compound (I).

2) A compound (I) can be produced by making react a compound represented by the general formula (IV):

6

in which the Ab ring represents a bicyclic condensed ring in which at least one of the rings is an aromatic ring and it has a lower acyl group or ux optionally together with substituent (s) optionally protected (s); the ring Bb represents pyrrole, 4H-1,4-oxazine or 4H-1,4-thiazine; the Cb ring represents a monocyclic aromatic ring that optionally has optionally protected substituent (s); e Y is as defined before,

with a carbonyl reducing agent.

The reduction can be done using a method commonly used to reduce carbonyl groups. The examples Preferable of such a method include catalytic reduction with use of a catalyst such as palladium-carbon and reduction with a borane / pyridine or borocyanohydride complex sodium

Next, a procedure for produce the starting compounds (II) to be used herein invention. The starting compounds (II) involve compounds known and new. New compounds can be produced applying or combining procedures to synthesize compounds acquaintances that have already been reported.

Production procedure one

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in which the ring Ac represents an optionally substituted non-aromatic monocyclic ring or a bicyclic condensed ring in which both rings are not aromatic; the ring Ad represents a ring formed totally or partially dehydrogenating the Ac ring; and the Ca ring, e and fa are each as defined before.

The compound represented by the general formula (IX) can be produced by applying, for example, the Fischer method to synthesize indole or the Borsche method to synthesize tetrahydrocarbazole [Org. Syn. IV, 884 (1963)]. Namely, it can obtained by heating a cyclic ketone represented by the formula (VII) and an aromatic carboxylic acid o-hydrazino in acetic acid or formic acid or in a neutral solvent such as ethanol in the presence of an acid catalyst such as acid hydrochloric, sulfuric acid or zinc chloride. When the Ac ring in compound (IX) is a bicyclic fused ring optionally substituted in which only one of the rings is a aromatic ring, can be condensed with a compound represented by the general formula (VI) to thereby give the compound intended (IIa). Compound (X) can be produced by dehydrogenating partially or totally the non-aromatic ring in the compound (IX) with a dehydrogenation agent. As a dehydrogenation agent, can be used for example 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, chloranil or palladium-carbon. Reaction can usually performed at room temperature or low heating. When the Ac ring is a bicyclic condensed ring in which both rings are non-aromatic, it is also possible selectively dehydrogenize one of these rings by selecting appropriately the type and quantity of the reagent, the conditions of reaction, etc. The intended compound (IIa) can be produced condensing the compound (X) thus obtained with the compound (VI). The condensation can be performed, for example, by the method of acid chloride, the active ester method or the method of mixed acid anhydride or using condensing agents such as 1,3-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole or diphenylphosphorylazide.

Production procedure 2

8

in which the Ae ring means a optionally substituted monocyclic aromatic ring or a ring bicyclic condensate in which at least the ring bearing the -G-H substituent is an aromatic ring; G represents an oxygen atom or a sulfur atom; K and L each one represents a labile group; R represents an alkyl group lower; and the ring Ca, e and fa are each as defined before.

The compound represented by the general formula (XIII) can be produced by reacting the compound of formula general (XI) with the compound of general formula (XII). They can cited respectively nitro and halogen as preferable examples of the labile groups K and L of the compound (XII). Reaction can be carried out by heating these compounds optionally in the presence of a base such as triethylamine, sodium acetate or hydroxide sodium The intended compound (IIb) can be produced by hydrolyzing an ester of compound (XIII) with an alkali to compound (XIV) and condensing this compound with the compound (VI) of the same way as the production procedure (I).

When the compound of the present invention has if used as medicine, it can be administered orally or parenterally. Although the dose is not particularly restricted It varies depending on the severity of the symptom, age, sex, body weight and patient sensitivity, method, the time and intervals of the administration, the properties, the  type and active ingredients of medicinal preparation, etc., It can usually be given to an adult in a daily dose of 1 at 3,000 mg, preferably about 10 to 2,000 mg and still preferably from 20 to 1,000 mg, in one to three portions per day.

To prepare a solid preparation for oral administration, the main agent is mixed with fillers and, if it is necessary, binders, disintegrating agents, lubricants, coloring agents, corrective agents, etc., and the mixture obtained is made in tablets, coated tablets, granules, subtitles fine, powders, capsules, etc. in a conventional way.

As fillers, for example, lactose can be used, cornstarch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide As binders, it can be used, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, acacia, hydroxypropylcellulose and hydroxypropylmethylcellulose. How lubricants, for example, magnesium stearate, talc can be used and silica As coloring agents, acceptable ones can be used pharmaceutically As corrective, they can be used, for example, cocoa powder, menthol, aromatic acids, peppermint oil piperita, Borneo camphor and powdered cinnamon bark. Is Needless to say, these pills or granules can be coated with sugar, jelly, etc., if needed.

To prepare injections, the main agent will mix, if necessary, with pH regulators, buffers, suspending agents, solubilizing agents, stabilizers, isotonizing agents, preservatives, etc. and the mix obtained is made in intravenous, subcutaneous or intramuscularly in a conventional manner. Then, these preparations they can be lyophilized in a conventional manner, if necessary.

As suspending agents, they can be used, by example, methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose and monolaurate of polyoxyethyl sorbitan.

As solubilizing agents, they can be used, by example, polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, and ethyl esters of macrogol fatty acids and oil of castor

As stabilizers, they can be used, for example, sodium sulphite and sodium metasulfite. As conservation agents, can be used, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol

Experimental examples are given below. pharmacological to illustrate the effects of the compounds of the present invention

Experimental example one

In vitro antitumor assay in P388 cells (mouse leukemic cells)

P388 cells suspended in medium were pipetted RPMI1640 (manufactured by Sanko Junyaku) containing 10% serum fetal calf, 100 U / ml penicillin, 100 µg / ml of Streptomycin, 5 x 10-5 M mercaptoethanol and 1 mM of sodium pyruvate in a 96-well U-bottom microplate in a ratio of 1.25 x 103 cells (0.1 ml) per well and incubated in an incubator containing 5% carbon dioxide at 37 ° C for one day.

A compound of the present invention dissolved in dimethyl sulfoxide to give a concentration of 10-2 M and then diluted with the culture medium RPMI1640 containing 10% fetal calf serum to give a concentration of 10-4 or 10-5 M. Taking this concentration as a maximum level, a serial dilution three times with the use of the culture medium RPMI1640 containing 10% fetal calf serum. They were added then these dilutions to the P388 incubation plate as described above in a ratio of 0.1 ml per well followed by incubation in an incubator containing 5% carbon dioxide at 37 ° C for 3 days.

After incubation was completed, 0.05 was added ml / well of a solution of 3.3 mg / ml MTT [bromide 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium] and incubation was continued for a further 2 hours. The centrifuge was centrifuged microplate and the supernatant was aspirated from each well. Later dissolved the formazan thus formed in 0.1 ml of sulfoxide of dimethyl and its absorbance at 540 nm measured with a reader of microplates was taken as an indication of cell count viable. According to the following formula, the relationship was calculated inhibitor and the 50% inhibitory concentration was determined (IC50) of the test compound:

relationship inhibitor (%) = \ frac {C-T} {C} x 100

in which T means the absorbance of a well containing the test compound and C means the absorbance of a well that does not contain the compound from test.

Table 1 summarizes the IC50 data obtained. So.

TABLE 1 In vitro anti-tumor assay in P388 cells

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Experimental example 2

In vivo antitumor assay in M5076 (mouse reticulum cell sarcoma)

M5076 cells were transplanted subcutaneously (1 x 106 / aimal) on the side of each BDF1 mouse (from 6 to 7 weeks old, females). A compound of the present invention is dissolved in a 5% glucose solution. From the next day at transplantation, the compound solution was administered intraperitoneally to animals once a day according to each Program. On the other hand, a control group was administered 5% glucose solution. The control group had 10 animals, while each test group had 5 animals.

On the 21st day after the transplant, the tumors and weighed. The inhibitory ratio of tumor multiplication from each test group to the control group according to the following formula:

relationship inhibitor (%) = \ frac {C-T} {C} x 100

in which T means the weight of mean tumor of the test group and C means the tumor weight middle of the group witness.

Table 2 shows the results of this experiment.

TABLE 2 In vivo anti-tumor test in M5076

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Experimental example 3

In vivo anti-tumor test on MX-1 (human breast cancer)

Pieces of tumor were subcutaneously transplanted MX-1 (approximately 1 mm3) to the side of each mouse devoid of immune system (BALB / C nu / nu, 6 to 7 weeks, females). A compound of the present invention dissolved in a 5% glucose solution. When the tumor volume reached 50 mm3 (on approximately the 10th day after the transplant), the compound solution was administered intraperitoneally to the animals once a day according to each program. On the other hand, it administered a 5% glucose solution to the control group. The group witness had 10 animals, while each test group had 5 animals

On the 22nd day after the transplant, the tumors and weighed. The inhibitory ratio of tumor multiplication from each test group to the control group according to the following formula:

relationship inhibitor (%) = \ frac {C-T} {C} x 100

in which T means the weight of mean tumor of the test group and C means the tumor weight middle of the group witness.

Table 3 shows the results of this experiment.

TABLE 3 In vivo anti-tumor test on MX-1

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As these experimental data show clearly, the compounds of the present invention have excellent anti-tumor effects and are thus useful as an agent antitumor

Example

Production examples are shown that show the production of the starting compounds used herein invention and Examples relating to typical examples of the compounds of the present invention. However, it should be understood that the The present invention is not restricted to them.

Production example one

Acid 5,6-dihydro-7H-benzo [c] carbazol-8-carboxylic

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A solution of 5.00 g (34.2 mmol) of β-tetralone in acetic acid (10 ml) is added dropwise to a suspension of 7.05 g (37.4 mmol) of 2-Hydrazinobenzoic acid hydrochloride in acid acetic acid (40 ml) at 80 ° C, and the obtained mixture was heated under reflux for 3 hours and 45 minutes. After returning to room temperature, water was added thereto and the precipitate formed  thus it was absorbed by filtration, washed with water, dried and dried. recrystallized from ethanol to thereby give 5.2 g of the compound of Title.

1H-NMR (DMSO-d6) δ (ppm): 2.91-3.06 (m, 4H), 7.03 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.20-7.27 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 11.29 (s, 1H).

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Production example 2

Acid 7H-benzo [c] carbazol-8-carboxylic

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3.29 g (14.3 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a suspension of 2.97 g (11.3 mmol) of the compound of Example of production 1 in benzene (200 ml) at room temperature, and the obtained mixture was stirred for 50 minutes and then heated under reflux for 3 hours and 20 minutes. After returning to room temperature, the precipitate thus formed was absorbed by filtration and recrystallized from ethanol to thereby give 2.76 g of title compound.

1H-NMR (DMSO-d6) δ (ppm): 7.39 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 8.00-8.07 (m, 3H), 8.79 (d, J = 7.3 Hz, 1H), 8.87 (d, J = 7.3 Hz, 1H), 11.82 (s, 1H), 13.22 (wide s, 1H).

Production example 3

N- [2- (Dimethylamino) ethyl] -7H-benzo [c] carbazol-8-carboxamide

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2.52 g (15.5 mmol) of N, N'-carbonyldiimidazole at a solution of 1.89 g (7.25 mmol) of the compound of Production Example 2 in dimethylformamide (60 ml) at room temperature, and the mixture obtained was stirred for 45 minutes. They were added later to it 5.0 ml (45.5 mmol) of N, N-dimethylethylenediamine and The resulting mixture was stirred for 2 hours and 40 minutes. After if concentrated, it was extracted by adding water and ethyl acetate. The organic layer was absorbed, washed with water, dried over sulfate sodium and concentrated to dryness to thereby give 2.47 g of the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.33 (s, 2H), 2.60 (t, J = 5.7 Hz, 2H), 3.63 (q, J = 5.7 Hz, 2H), 7.16 (wide s, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.46-7.50 (m, 1H), 7.65-7.73 (m, 3H), 7.89 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 8.69 (d, J = 7.5 Hz, 1H), 8.74 (d, J = 8.2 Hz, 1H), 10.94 (wide s, 1H).

Production example 4

Acid 3-acetyl-7H-benzo [c] carbazol-8-carboxylic

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1.17 ml (12.4 mmol) of anhydride was added acetic to a suspension of 5.1 g (38 mmol) of chloride aluminum in dichloromethane (300 ml) at 0 ° C, and the mixture obtained is stirred for 20 minutes. 2.16 g were then added thereto. (8.28 mmol) of the compound of Production Example 2, and the mixture  obtained was stirred at the same temperature for 4 hours and 30 minutes The reaction mixture was then poured into ice water and It was extracted with a mixture of chloroform with ethanol. The layer Organic was absorbed and concentrated. The residue was purified by silica gel column chromatography to give 1.45 g of the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.72 (s, 3H), 7.44 (t, J = 7.6 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.18 (dd, J = 1.9, 8.8 Hz, 1H), 8.79 (d, J = 1.9 Hz, 1H), 8.87 (d, J = 8.8 Hz, 1H), 8.91 (d, J = 7.6 Hz, 1H), 12.01 (s, 1H).

Production example 5

3-Acetyl-N- [2- (dimethylamino) ethyl] -7H-benzo [c] carbazol-8-carboxamide

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291 mg (1.80 mmol) of N, N'-carbonyldiimidazole at a solution of 247 mg (0.815 mmol) of the compound of Production Example 4 in dimethylformamide (7 ml) under ice cooling. After return to room temperature, the obtained mixture was stirred for about 2 hours 0.45 ml was then added thereto. (4.1 mmol) of N, N-dimethylethylenediamine and the resulting mixture was returned to room temperature and stirred at room temperature for about 12 hours. After extract by adding water and chloroform, the organic layer was absorbed, dried over sodium sulfate and concentrated to dryness. It was purified then the residue by silica gel column chromatography to thereby give 140 mg of the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.29 (s, 6H), 2.53-2.61 (m, 2H), 2.74 (s, 2H), 3.52 (q, J = 5.9 Hz, 2H), 7.43 (t, J = 7.1 Hz, 1H), 7.97 (d, J = 7.1 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.20 (dd, J = 1.8, 8.5 Hz, 1H), 8.72 (t, J = 5.9 Hz, 1H), 8.79-8.83 (m, 2H), 8.88 (d, J = 8.5 Hz, 1H), 12.17 (s, 1 H).

Production example 6

3,4,5,8-Tetrahydronaphthalene-1.6 (2H, 7H) -dione

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6.8 g (38.2 mmol) of 1,2,3,4,5,8-hexahydro-1-oxo-6-methoxynaphthalene in 50 ml of tetrahydrofuran and 5 ml of acid was added thereto 1 N hydrochloric acid. After stirring at room temperature for 1 hour, ethyl acetate was added thereto. The mixture was then washed. of reaction with a saturated aqueous solution of sodium chloride and Dry over magnesium sulfate. After concentrating, it was added to it a small amount of a mixture of n-hexane with ethyl acetate (1: 1) and the mixture obtained was cooled in a dry ice-ether bath. The precipitate thus formed was recovered by filtration and washed in a small amount of n-hexane to thereby give 4.8 g of the compound of Title.

1H-NMR (CDCl3) δ (ppm): 2.01-2.11 (m, 2H), 2.30-2.37 (m, 2H), 2.45-2.51 (m, 4H), 2.68-2.76 (m, 2H), 3.05 (s, 2H).

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Production example 7

Acid 4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazol-8-carboxylic

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18

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5.4 g (28.6 mmol) of 2-hydrazinobenzoic acid hydrochloride and 4.7 g (34.3 mmol) of zinc chloride were added to 300 ml of glacial acetic acid. Under stirring at approximately 85 ° C, 4.7 g (28.6 mmol) of the compound of Production Example 6 were added thereto for approximately 5 minutes. The mixture obtained was then stirred at the same temperature for approximately 2 hours, returned to room temperature and the precipitate was recovered by filtration. After concentrating the filtrate, water was added thereto and the precipitate thus formed was recovered by filtration. These precipitates were combined, dried and then dissolved in approximately 500 ml of dimethylformamide. Under stirring at room temperature, a solution of 6.5 g (28.6 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in tetrahydrofuran (20 ml) was added thereto and the mixture obtained was stirred for approximately 30 minutes. After concentrating, approximately 50 ml of ethanol was added and the precipitate thus formed was recovered by filtration to thereby give 3.4 g of the compound of the
Title.

1H-NMR (DMSO-d6) δ (ppm): 2.17-2.29 (m, 2H), 2.63-2.70 (m, 2H), 3.55 (t, J = 6.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.06 (dd, J = 0.8, 7.6 Hz, 1H), 8.48 (dd, J = 0.8, 7.6 Hz, 1H),  11.83 (s, 1H), 13.33 (wide s, 1H).

Production example 8

N- [2- (Dimethylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazol-8-carboxamide

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19

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3.4 g (12.2 mmol) of the compound were added of Production Example 7 to 120 ml of dimethylfomamide and stirred. Then, a solution of 3.0 g (18.5 was added thereto) mmoles) of N, N'-carbonyldiimidazole in dimethylformamide (30 ml). After stirring at room temperature for 1 hour, 3.2 g (36.3 mmol) of N, N-dimethylethylenediamine. After shaking the same temperature for another hour, the mixture of reaction and ethyl acetate was added thereto. Washed after successively with dilute aqueous ammonia and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness to thereby give 4.3 g of the title compound.

FAB mass spectrometry m / z: 350 ([M + H] +).

1H-NMR (CDCl3) δ (ppm): 2.30-2.40 (m + s, 2H + 6H), 2.62 (t, J = 6.0 Hz, 2H), 2.74-2.79 (m, 2H), 3.56-3.66 (m, 4H), 7.21 (wide s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 0.8, 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 0.8, 8.0 Hz, 1H), 10.91 (wide s, 1H).

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Production example 9

Acid 2,3-dihydro-3-oxo-1H, 6H-cyclopenta [c] carbazol-7-carboxylic

twenty

The title compound was obtained by making react 2,3,4,7-tetrahydro-1H-indene-1,5 (6H) -dione, that had been synthesized from 2,3,4,7-tetrahydro-5-methoxy-1H-inden-1-one by the same method as in Production Example 6, in the same way so as in Production Example 7.

FAB mass spectrometry m / z: 266 ([M + H] +).

1H-NMR (DMSO-d6) δ (ppm): 2.70-2.82 (m, 2H), 3.52-3.62 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 0.8, 7.6 Hz, 1H), 11.95 (s, 1H), 13.37 (wide s, 1H).

Production example 10

2,3-Dihydro-N- [2- (dimethylamino) ethyl] -3-oxo-1H, 6H-cyclopenta [c] carbazol-7-carboxamide

twenty-one

The title compound was obtained from compound of Production Example 9 by the same method as that of Production example 8.

FAB mass spectrometry m / z: 366 ([M + H] +).

1H-NMR (CDCl3) δ (ppm): 2.34 (s, 6H), 2.61 (t, J = 6.0 Hz, 2H), 2.85-2.91 (m, 2H), 3.58-3.66 (m, 4H), 7.18 (wide s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 10.95 (s wide, 1H).

Production example eleven

5,6,7,8-Tetrahydro-9H-carbazol-1-carboxylate of methyl

22

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A solution of 28 ml (0.270 mol) of cyclohexanone in acetic acid (100 ml) was added dropwise to a 52 g suspension (0.276 mol) of acid hydrochloride 2-Hydrazinobenzoic acid acetic acid (500 ml) at 100 ° C and the obtained mixture was heated under reflux for 6 hours. After returning to room temperature, 1 l of water and the precipitate thus formed was absorbed by filtration, it washed with water and dried to give 43 g of a powder. This powder was then dissolved in 500 ml of acetone. After adding to it 37.5 ml (0.602 mol) of methyl iodide and 41.4 g (0.300 moles) of anhydrous potassium carbonate, the reaction mixture is heated under reflux for 2 hours. After returning to room temperature, insoluble materials were separated by filtration. After concentrating the filtrate, it was added thereto. water and the precipitate thus formed was recovered by filtration to give therefore 45.7 g of the title compound.

1H-NMR (CDCl3) δ (ppm): 1.85-1.97 (m, 4H), 2.70-2.74 (m, 2H), 2.76-2.80 (m, 2H), 3.97 (s, 3H), 7.09 (t, J = 7.6 Hz, 1H), 7.65-7.68 (m, 1H), 7.79 (dd, J = 1.1, 7.6 Hz, 1H), 9.39 (wide s, 1H).

Production example 12

5-Oxo-5,6,7,8-tetrahydro-9H-carbazol-1-carboxylate of methyl

2. 3

45.7 g (0.199 mol) of the compound were dissolved of Production Example 11 in a mixture of tetrahydrofuran (500 ml) with water (50 ml). It was added dropwise to the solution obtained a solution of 90.8 g (0.400 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in tetrahydrofuran (200 ml) under a low nitrogen atmosphere ice cooling After stirring at room temperature for 3 hours, 1 l of an aqueous solution of potassium carbonate followed by extraction with ethyl acetate. Be then absorbed the organic layer, washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to thereby give 39.7 g of the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.10-2.17 (m, 2H), 2.44-2.48 (m, 2H), 3.07 (t, J = 6.2 Hz, 2H), 3.96 (s, 3H), 7.28 (t, J = 7.7 Hz, 1H), 7.81 (dd, J = 1.3, 7.7 Hz, 1H), 8.25 (dd, J = 1.3, 7.7 Hz, 1H), 11.79 (wide s, 1H).

Production example 13

5-Hydroxy-9H-carbazol-1-carboxylate of methyl

24

39.1 g (0.161 moles) of the compound of Production Example 12 in diphenyl ether (150 ml). After adding 10 g of 10% palladium-carbon, mix obtained was heated under reflux under nitrogen atmosphere for 3  hours. After allowing to cool, the precipitated crystals well and palladium-carbon recovered by filtration and washed with hexane. Then, the recovered mixture dissolved in hot tetrahydrofuran and filtered off palladium-carbon After concentrating, the residue was recrystallized from ethanol to thereby give 34.7 g of title compound.

1H-NMR (CDCl3) δ (ppm): 4.03 (s, 3H), 5.54 (s, 1H), 6.62 (dd, J = 0.6, 7.9 Hz, 1H), 7.10 (dd, J = 0.6, 7.9 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 8.05 (dd, J = 1.2, 7.9 Hz, 1H), 8.46-8.50 (m, 1H), 9.93 (wide s, 1H).

Production example 14

Acid [1-methoxycarbonyl-9H-carbazol-5-yl] oxyacetic

25

34.8 g (0.144) were dissolved in acetone (550 ml) moles) of the compound of Production Example 13. After adding thereto 68.5 ml (0.432 mol) of benzyl bromoacetate, 64.8 g (0.432 moles) of sodium iodide and 29.8 g (0.216 moles) of carbonate anhydrous potassium, the mixture obtained was heated under reflux for 60 hours After allowing to cool, the precipitate formed in this way was filtered off followed by concentration. Be then extracted by adding ethyl acetate and water and the layer organic was absorbed, washed with water, dried over sulfate magnesium and concentrated. It was added to the obtained residue n-hexane to solidify it. He recovered then by filtration and recrystallized from ethanol to thereby give  40.7 g of benzyl ester of the title compound. This product it was suspended in a mixture of tetrahydrofuran (600 ml) and methanol (500 ml). Next, 12 g of palladium was added thereto 10% carbon and the product was hydrogenated under atmospheric pressure at ordinary temperature to thereby give 29.4 g of the compound of Title.

1H-NMR (CD3OD) δ (ppm): 4.02 (s, 3H), 4.90 (s, 2H), 6.67 (dd, J = 0.6, 8.0 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.26 (dd, J = 0.6, 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 8.02 (dd, J = 1.1, 7.7 Hz, 1H), 8.63 (dd, J = 1.1, 7.7 Hz, 1H), 10.87 (wide s, 1H).

Production example fifteen

Acid 2,3-dihydro-3-oxo-6H-furo [3,2-c] carbazol-7-carboxylic

26

They were suspended in toluene (500 ml) 29.4 g (0.098 moles) of the compound of Production Example 14. After adding 36 ml (0.494 mol) of thionyl chloride, the mixture obtained is heated under reflux until it became homogeneous. After concentrate, dissolved by adding 500 ml of dichloromethane thereto, and 32.1 g (0.240 mol) of chloride were added thereto aluminum while stirring under ice cooling. Turned then at room temperature, it was stirred overnight and then added to it ice water under ice cooling. After stirring at room temperature, it was concentrated and added to it diluted hydrochloric acid. The precipitate was recovered by filtration, washed successively with water and ethanol and dried to give therefore 26.5 g of a powder. The whole powder dissolved in a mixture of tetrahydrofuran (350 ml) with methanol (250 ml) and 750 ml of a 0.2 N aqueous solution was added thereto degassed sodium hydroxide under nitrogen atmosphere. After hydrolyzing the ester at 50 ° C, 20 ml of concentrated hydrochloric acid. It was then extracted with a mixture of ethyl acetate with tetrahydrofuran and the organic layer is absorbed, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography of silica gel to thereby give 11.4 g of the title compound.

1H-NMR (DMSO-d6) δ (ppm): 5.00 (s, 2H), 7.41 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 8.07 (dd, J = 1.3, 7.7 Hz, 1H), 8.29-8.32 (m, 1H), 12.10 (wide s, 1H).

Production example 16

N- [2- (Allylmethylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazol-8-carboxamide

27

Starting from 0.5 g (1.79 mmol) of the compound of Production Example 7 and 0.53 g (7.15 mmol) of N-Methylethylenediamine, 0.49 g of N- [2- (methylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazol-8-carboxamide by the same method as in Production Example 8. It dissolved in tetrahydrofuran (30 ml) 0.49 g (1.46 mmol) of this product, 0.25 g (1.74 mmol) of allyl bromide and 0.23 g (1.78 mmoles) of N, N-diisopropylethylamine and stirred at 55 ° C for about 5 hours. After allowing to cool, diluted with ethyl acetate, washed successively with ammonia Diluted aqueous and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography to thereby give 0.24 g of the title compound.

\hbox{J =}

8,4 Hz, 1H), 7,67 (dd, J = 0,8, 7,6 Hz, 1H), 8,25 (d, J = 8,4 Hz, 1H), 8,33 (dd, J = 0,8, 7,6 Hz, 1H), 10,88 (s ancho, 1H).1H-NMR (CDCl3) δ (ppm): 2.28-2.40 (m + s, 2H + 3H), 2.70 (t, J = 6.0 Hz, 2H), 2.73-2 , 80 (m, 2H), 3.11-3.17 (m, 2H), 3.56-3.68 (m, 4H), 5.17-5.29 (m, 2H), 5.82 -5.97 (m, 1H), 7.24 (broad s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.42 (d,

 \ hbox {J =} 

8.4 Hz, 1H), 7.67 (dd, J = 0.8, 7.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 0.8, 7.6 Hz, 1H), 10.88 (wide s, 1H).

Production example 17

5- [1- (Allylmethylamino) ethyl] -12,13-dihydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6,10 (5H, 11H) -trione

28

Starting from 0.24 g (0.64 mmol) of the compound of Production Example 16, 0.23 g of the compound of the title by the same method as in Example 2, although omitting the hydrochloride procedure.

1H-NMR (CDCl3) δ (ppm): 2.32-2.42 (m + s, 2H + 3H), 2.73-2.84 (m, 4H), 3.10-3.15 (m, 2H), 3.53 (t, J = 6.4 Hz, 2H), 4.35 (t, J = 7.2 Hz, 2H), 5.08-5.22 (m, 2H), 5.74-5.90 (m, 1H), 7.63 (t, J = 7.6 Hz, 1H), 8.19 (dd, J = 0.8, 7.6 Hz, 1H), 8.32 (dd, J = 0.8, 7.6 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H).

Production example 18

6-Methyl-9H-carbazol-1-carboxylate of methyl

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29

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A suspension of 2.0 g (10.6 mmol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (20 ml) was slowly boiled under stirring and 1.2 ml (9.8 mmol) of water was added dropwise. 4-methylcyclohexanone. The obtained mixture was heated under reflux for 8 hours and then allowed to cool. After adding water, the precipitate thus formed was recovered by filtration, washed with water and dried to thereby give 1.96 g of 6-methyl-5,6,7,8-tetrahydro-9H-carbazol-1 acid. -carboxylic. This product was dissolved in acetone (50 ml) and 2.1 ml (34 mmol) of methyl iodide and 2.35 g (17 mmol) of anhydrous potassium carbonate were added thereto. The reaction mixture was heated under reflux with stirring for 2 hours, then allowed to cool and extracted with water and ethyl acetate. The organic layer was absorbed, washed with water, dried over magnesium sulfate and concentrated to dryness. 1.49 g of methyl 6-methyl-5,6,7,8-tetrahydro-9H-carbazol-1-carboxylate were thus obtained. This product was suspended in diphenyl ether (10 ml) and 890 mg of 10% palladium-carbon was added thereto. The obtained mixture was heated under reflux and stirring under a nitrogen atmosphere for 1 hour. After allowing it to cool, it was dissolved by adding tetrahydrofuran. Then, the catalyst was filtered off and the filtrate was concentrated. After adding n-hexane, the crystals thus formed were recovered by filtration to thereby give 1.26 g of the compound of the
Title.

1H-NMR (CDCl3) δ (ppm): 2.54 (s, 3H), 4.02 (s, 3H), 7.22 (t, J = 7.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.87-7.90 (m, 1H), 8.05 (dd, J = 1.1, 7.8 Hz, 1H), 8.21-8.25 (m, 1H), 9.82 (wide s, 1H).

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Production example 19

6-Formyl-9H-carbazol-1-carboxylate of methyl

30

1.8 g (10 mmol) of N-Bromosuccinimide and 220 mg (1.3 mmol) of α, α'-azobisisobutyronitrile at a 1.2 g solution (5 mmol) of the compound of the Example of Production 18 in carbon tetrachloride (100 L) and the mixture obtained was heated under reflux and stirring for 1 hour. After  if allowed to cool, the mixture was concentrated and the residue was purified by silica gel column chromatography to give for it 1.13 g of the title compound.

1H-NMR (CDCl3) δ (ppm): 4.05 (s, 3H), 7.36 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 8.03 (dd, J = 1.6, 8.4 Hz, 1H), 8.14 (dd, J = 1.2, 7.8 Hz, 1H), 8.32-8.36 (m, 1H), 8.62-8.64 (m, 1H), 10.12 (s, 1H), 10.23 (wide s, 1H).

Production example twenty

1,2-Dihydro-1-oxo-7H-pyrido [4,3-c] carbazol-8-carboxylate of methyl

31

2.6 g (25 mmol) of malonic acid were added and 0.3 ml of piperidine to a solution of 2.0 g (7.9 mmol) of compound of Production Example 19 in pyridine (80 ml) and the obtained mixture was stirred in a bath at 80 ° C for 1 hour. Be then added thereto under heating and stirring for 1 hour 2.6 g (25 mmol) of malonic acid and the mixture obtained is heated under reflux for 1 more hour. After letting cool, the reaction mixture was poured into hydrochloric acid ice-concentrate and the precipitate thus formed recovered by filtration, washed with water and dried to give it 1.8 g of acid 3- (1-Methoxycarbonyl-9H-carbazol-6-yl) acrylic.  The compound obtained was dissolved in acetone (70 ml) and added 2 ml of triethylamine thereto. They were added dropwise to it under ice cooling and stirring 0.64 ml (6.7 mmol) of ethyl chloroformate and the reaction mixture was then stirred at same temperature for 1 hour. Then, drop was added to drop to it under ice cooling and stirring a solution of 870 mg (12 mmol) of sodium azide (90%) in 20 ml of water. The reaction mixture was stirred at the same temperature for 1 hour and It was then poured on ice. The precipitate thus formed was recovered. by filtration This precipitate was added together with 3 ml of tributylamine to diphenyl ether (20 ml) and heated to 260 ° C. After if allowed to cool, hexane was added thereto and the precipitate formed thus it was recovered by filtration and washed successively with n-hexane and ethanol to give 1.39 g of the title compound.

1H-NMR (DMSO-d6) δ (ppm): 4.01 (s, 3H), 6.73 (t, J = 7.0 Hz, 1H), 7.18-7.24 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 8.08 (dd, J = 1.3, 7.9 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 10.13 (dd, J = 1.3, 7.9 Hz, 1H), 11.36-11.42 (m, 1H), 11.93 (wide s, 1H).

Production example twenty-one

7H-Pyrido [4,3-c] carbazol-8-carboxylate of methyl

32

10 ml of phosphorus oxychloride was added to 1.19 g (4 mmol) of the compound of Production Example 20 and the obtained mixture was heated under reflux. The mixture 3 was poured hours later on ice and neutralized with sodium bicarbonate. Be then extracted with dichloromethane. The organic layer was absorbed, it washed with water, dried over magnesium sulfate and concentrated. He residue was purified by silica gel column chromatography to give 390 mg of 1-Chloro-7H-pyrido [4,3-c] carbazol-8-carboxylate of methyl This product was dissolved in a mixture of tetrahydrofuran with methanol and 1 ml of triethylamine The hydrogenation was then carried out in the presence of palladium-carbon under atmospheric pressure a ordinary temperature to thereby give 300 mg of the compound of the Title.

1H-NMR (DMSO-d6) δ (ppm): 4.04 (s, 3H), 7.48 (t, J = 7.7 Hz, 1H), 8.00 (d, J = 5.4 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 5.4 Hz, 1H), 9.06 (d, J = 7.7 Hz, 1H), 10.22 (s, 1H), 12.11 (wide s, 1H).

Production example 22

Acid 10-nitro-7H-benzo [c] phenothiazine-8-carboxylic

33

5 ml of a 2N aqueous solution of sodium hydroxide to a solution of 1.7 g (9.73 mmol) of 2-amino-1-naphthalenothione in ethanol (30 ml) and the mixture obtained was heated under reflux. Be 2.54 g (9.76 mmol) of 2-Chloro-3,5-Dinitrobenzoate of methyl and the mixture obtained was heated under reflux for 1 hour. 10 ml of a 2N aqueous solution was added to this mixture. of sodium hydroxide and 40 ml of ethanol, and the mixture obtained is heated under reflux for 10 more hours. He later turned to room temperature and concentrated. After adding water, it slowly added to it under stirring 1 N hydrochloric acid to therefore regulate the pH value at approximately 1. The precipitate was recovered by filtration and washed successively with ethanol and methanol to thereby give 1.14 g of the compound of Title.

1H-NMR (DMSO-d6) δ (ppm): 7.04 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 8.35 (s, 1H), 11.37 (wide s, 1H).

Production example 2. 3

N- [2- (Dimethylamino) ethyl] -10-nitro-7H-benzo [c] -phenothiazine-8-carboxamide

3. 4

10 ml of trichloride was successively added phosphorus and 2 ml of dimethylformamide at a suspension of 1.82 g (5.39 mmoles) of the compound of Production Example 22 in chloroform (60 ml) at 0 ° C. It then turned slowly at room temperature and stirred overnight. After completely distilling the solvent of the mixture under reduced pressure, was added to the residue 30 ml dichloromethane. While stirring at 0 ° C, it added a solution of 5 ml of dropwise to the mixture N, N-dimethylethylenediamine in dichloromethane (30 ml). The reaction mixture was then slowly turned to temperature ambient and stirred at room temperature for 7 hours, A Then, water and an aqueous solution were added thereto. saturated with sodium hydrogen carbonate, and the mixture obtained is stirred and filtered through celite to eliminate from it for that reason the insoluble matters. The organic layer was absorbed, washed successively with water and a saturated aqueous chloride solution Sodium, dried over anhydrous magnesium sulfate, concentrated to dryness and recrystallized from ethanol to thereby give 956 mg of title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.20 (s, 6H), 2.45 (t, J = 6.0 Hz, 2H), 3.37 (t, J = 6.0 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.93 (wide s, 1H), 8.39 (d, J = 2.9 Hz, 1H), 9.50 (wide s, 1H).

Production example 24

Acid 3- (4-methylbenzenesulfonamido) -7H-benzo [c] carbazol-8-carboxylic

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35

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The title compound was obtained by making react acid 5,6-dihydro-3- (4-methylbenzenesulfonamido) -7H-benzo [c] carbazol-8-carboxylic acid, that had been obtained by heating under reflux 6- (4-methylbenzenesulfonamido) -2-tetralone and 2-hydrazinobenzoic acid hydrochloride in xylene, in the same way as in Production Example 2.

\hbox{J =}

8,8 Hz, 1H), 8,66 (d, J = 8,8 Hz, 1H), 8,79 (d, J = 8,0 Hz, 1H), 10,33 (s, 1H), 11,76 (s, 1H).1H-NMR (DMSO-d6) δ (ppm): 2.26 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.35 (dt, J = 2.0 , 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 6.8 Hz, 2H), 7.71 (s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.96 (dd, J = 2.0, 9.2 Hz, 1H), 8.01 (d,

 \ hbox {J =} 

8.8 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 10.33 (s, 1H), 11 , 76 (s, 1 H).

Production example 25

13H-benz [6,7] indole [2,3-c] quinoline-12-carboxylate of ethyl:

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36

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A suspension of 4.24 g (22.5 mmol) of 1-Naphthylhydrazine hydrochloride in acetic acid (35 ml) was boiled slowly and added dropwise thereto under stirring a solution of 3.4 g (20.6 mmol) of 2-nitrophenylacetaldehyde in acetic acid (15 ml). After completion of the drip, the mixture obtained was heated under reflux for 1 hour. They were added further to it 20 ml of a mixture of 1 N hydrochloric acid with acetic acid and the obtained mixture was heated under reflux for another 1 hour. After if the solvent was distilled off, the residue was dissolved by adding to it ethyl acetate. The organic layer was washed successively with a aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, and dried over sulfate anhydrous magnesium After distilling the solvent, the residue is purified by silica gel column chromatography to give 1.91 g (yield: 32%) of 7- (2-nitrophenyl) benz [g] indole. Then, the product obtained was dissolved in ethyl acetate (60 ml) and 200 mg of platinum (IV) oxide was added thereto. Be then performed the catalytic reduction under atmospheric pressure in an atmosphere of hydrogen at room temperature to give for it 1.7 g (yield: 99%) of 7- (2-aminophenyl) benz [g] indole.

Then, 20 ml of ethanol was added to 540 mg (2.1 mmol) of 7- (2-aminophenyl) benz [g] indole and 260 mg (2.5 mmol) of ethyl glyoxylate (polymer) and the mixture obtained was heated under reflux for 8 hours. After distill the solvent, the residue was purified by chromatography of silica gel column to give 380 mg (yield: 53%) of the title compound.

1H-NMR (CDCl3) δ (ppm): 1.64 (t, J = 7.1 Hz, 3H), 4.74 (q, J = 7.1 Hz, 2H), 7.63-7.77 (m, 3H), 7.79 (d, J = 8.6 Hz, 1H), 7.79-7.85 (m, 1H), 8.06 (dd, J = 1.3, 7.7 Hz, 1H), 8.35 (dd, J = 0.7, 8.1 Hz, 1H), 8.45 (dd, J = 1.3, 8.4 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 8.79 (dd, J = 1.1, 8.2 Hz, 1H), 10.98 (s wide, 1H).

Example 1 Hydrochloride 5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

37

457 mg (10.5 mmol) of hydride were added sodium (55% oily) to a solution of 1.44 g of the compound of Production example 3 in dimethylformamide (50 ml) at temperature ambient and the mixture obtained was stirred for 50 minutes. Be then added 1 ml (10.5 mmol) of ethyl chloroformate to it 0 ° C and the mixture obtained was stirred at the same temperature for 2 hours and then at room temperature for 6 hours. After add water, the precipitate was recovered by filtration, washed with water and dried. It was then dissolved in a dichloromethane mixture with methanol and insoluble matters were filtered off. After concentrating, ethanol and concentrated hydrochloric acid. The hydrochloride formed thus is recovered by filtration and recrystallized from ethanol to give 1.24 g of the title compound.

Mp .: 254-255 ° C (recrystallized in ethanol).

FAB mass spectrometry m / z: 358 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.90 (d, J = 5.5 Hz, 6H), 3.49 (q, J = 5.5 Hz, 2H), 4.42 (t, J = 5.5 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 8.0 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 9.70 (wide s, 1H).

Elementary analysis: how C22H19N3O2 \ cdotHCl \ cdotH2O

C H N calculated 64.15 5.38 10.20 found 64.38 5.05 10.22

Example 2 Hydrochloride 11-acetyl-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

38

13.2 mg (0.549 mmol) of hydride was added sodium to a solution of 105 mg (0.282 mmol) of the compound of Production example 5 in dimethylformamide (2.5 ml) at 0 ° C and the obtained mixture was stirred at the same temperature for 1 hour and 10 minutes and then at room temperature for 1 hour. Be then added to it 53.6 µl (0.564 mmol) of ethyl chloroformate at 0 ° C and the obtained mixture was stirred at same temperature for 1 hour and 20 minutes. After extracting adding water and chloroform, the organic layer was absorbed, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography and became its hydrochloride using 1 N hydrochloric acid (ethanol) to thereby give 106 mg of the title compound.

P.f .: colored from about 240 ° C and decomposed at about 250-254 ° C.

Mass spectrometry FAB m / z: 400 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.78 (s, 3H), 2.90 (s, 6H), 3.48-3.54 (m, 2H), 4.44 (t, J = 5.6 Hz, 2H), 7.80 (t, J = 7.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8.24 (dd, J = 2.3, 9.4 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 8.68 (d, J = 8.9 Hz, 1H), 8.87-8.91 (m, 2H), 9.01 (d, J = 7.5 Hz, 1H), 9.88 (s wide, 1H).

Elementary analysis: how C24H21N3O3 \ cdotHCl \ cdotH2O

C H N calculated 63.50 5.33 9.26 found 63.42 5.04 9.16

Example 3 Hydrochloride 5- [2- (dimethylamino) ethyl] -11- (1-hydroxyethyl) -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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39

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21 µL (0.168 mmol) of a borane / pyridine complex (approximately 8 M) to a suspension of 84 mg (0.211 mmol) of a compound prepared by converting the compound of Example 2 in its free base in acetic acid (1.5 ml) and the obtained mixture was stirred at 70 ° C for 3 hours. Was acidified then adding 1 N hydrochloric acid to it at temperature ambient, stirred for 1 minute and neutralized with a saturated aqueous sodium bicarbonate solution. Then, it extracted by adding a mixture of dichloromethane with ethanol. The organic layer was absorbed, washed with water, dried over sulfate sodium and concentrated. The residue was purified by chromatography of preparative thin layer and became its hydrochloride using acid 1 N hydrochloric to thereby give 44 mg of the compound of Title.

Mp .: 247 ~ 248 ° C (decomposition) (recrystallized from ethanol)

FAB mass spectrometry m / z: 402 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 1.50 (d, J = 5.0 Hz, 3H), 2.92 (s, 6H), 3.49 (t, J = 5.7 Hz, 2H), 4.43 (t, J = 5.7 Hz, 2H), 4.95-5.05 (m, 1H), 5.45 (d, J = 4.2 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 8.08-8.15 (m, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.59 (dd, J = 1.4, 8.4 Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.99 (d, J = 7.6 Hz, 1H), 9.90 (wide s, 1H).

Elemental analysis: as C24H24N3O3Cl

C H N calculated 65.82 5.52 9.60 found 65.49 5.53 9.49

Example 4 Hydrochloride 12,13-dihydro-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6,10 (5H, 11H) -trione

40

A solution of 4.9 g (14 mmol) of the compound of Production Example 8 in dimethylformamide (70 ml) was added dropwise to a suspension of 0.9 g (37.5 mmol) of hydride sodium in dimethylformamide (30 ml) at room temperature, and the obtained mixture was stirred at the same temperature for 2 hours. Be then added 2.5 g (23 mmol) of ethyl chloroformate to it under ice cooling and stirring. 15 was added to it minutes later ethyl acetate, and the obtained mixture was washed successively with dilute aqueous ammonia and an aqueous solution of sodium chloride, and dried over magnesium sulfate. After concentrate, methanol was added thereto and crystals were recovered by filtration. These crystals were then suspended in methanol and were acidified by adding thereto under stirring 1N hydrochloric acid. After stirring at room temperature and concentrating, it was added to it ethanol and the precipitate thus formed was recovered by filtration to thereby give 4.3 g of the title compound.

P.f .: colored from about 250 ° C, decomposed gradually from about 260 ° C and decomposed quickly at about 273-275 ° C.

FAB mass spectrometry m / z: 376 ([M + H] +)

\hbox{J =}

8,8 Hz, 1H), 8,61 (dd, J = 0,8, 7,6 Hz, 1H), 9,52 (s ancho, 1H).1H-NMR (DMSO-d6) δ (ppm): 2.22-2.36 (m, 2H), 2.72-2.80 (m, 2H), 2.92 (s, 6H), 3 , 44-3.54 (m, 2H), 3.54-3.60 (m, 2H), 4.38-4.46 (m, 2H), 7.75 (t, J = 7.6 Hz , 1H), 8.17 (dd, J = 0.8, 7.6 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.41 (d,

 \ hbox {J =} 

8.8 Hz, 1H), 8.61 (dd, J = 0.8, 7.6 Hz, 1H), 9.52 (wide s, 1H).

Elementary analysis: how C22H21N3O3 \ cdotHCl \ cdot1H2O

C H N calculated 61.47 5.63 9.77 found 61.47 5.57 9.77

Example 5 5- [2- (Dimethylamino) ethyl] -10-hydroxy-10,11,12,13-tetrahydro4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

41

0.5 g (1.2 mmol) of the compound was dissolved of Example 4 in a mixture of water (50 ml) with methanol (25 ml) and 1.2 ml of 1 N hydrochloric acid was added thereto. carried out hydrogenation in the presence of palladium-carbon under a hydrogen pressure of approximately 4.5 kg / cm2. After confirming that he had the reaction completed by thin layer chromatography, separated by filtration and catalyst and the residue was concentrated to about 2/3. After adding 50 ml of water and 5 ml to it of concentrated aqueous ammonia, the obtained mixture was extracted with ethyl acetate. The organic layer was absorbed, washed with a aqueous sodium chloride solution, dried over magnesium sulfate and He concentrated. The residue was purified by column chromatography. silica gel to thereby give 0.35 g of the compound of Title.

Mass spectrometry FAB m / z: 378 ([M + H] +)

1H-NMR (CDCL3) δ (ppm): 1.92-2.30 (m, 4H), 2.37 (s, 6H), 2.70 (t, J = 6.8 Hz, 2H), 3.06-3.32 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H), 4.95 (wide t, J = 4.8 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 0.8, 7.6 Hz, 1H), 8.15 (dd, J = 0.8, 7.6 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H).

Elementary analysis: how C22H23N3O3 \ cdot1H2O

C H N calculated 66.82 6.37 10.63 found 67.10 6.03 10.34

Example 6 (+) - 5- [2- (Dimethylamino) ethyl] -10-hydroxy-10,11,12,13-tetrahydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -diona

42

The compound of Example 5 was resolved with a optical resolution column [Chiralcel OD, manufactured by Daicel; eluted with n-hexane / 2-propanol (7: 3-6: 4). The fraction eluted sooner concentrated to dryness to thereby give the title compound.

Mp .: 160 \ sim162 ° C

Mass spectrometry FAB m / z: 378 ([M + H] +)

1H-NMR (CDCL3) δ (ppm): 1.90-2.30 (m, 4H), 2.43 (s, 6H), 2.77 (t, J = 6.4 Hz, 2H), 3.04-3.31 (m, 2H), 4.34 (t, J = 6.8 Hz, 2H), 4.95 (wide t, J = 4.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H).

Elementary analysis: how C22H23N3O3 \ 0.75H2O

C H N calculated 67.59 6.32 10.75 found 67.34 5.93 10.48

Rotation angle [α] D27: + 9.8º (c = 1.0, CHCl3).

Example 7 Hydrochloride 11,12-dihydro-5- [2- (dimethylamino) ethyl] -4H, 10H-cyclopenta [c] pyrimido [5,6,1-jk] carbazol-4,6,10 (5H) -trione

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43

The title compound was obtained from compound of Production Example 10 by the same method as the of Example 2.

P.f .: colored from about 255 ° C and decomposed gradually from about 265 ° C.

FAB mass spectrometry m / z: 362 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.83-2.94 (m, 8H), 3.45 (wide s, 2H), 3.64 (wide t, J = 6.0 Hz, 2H), 4.42 (wide t, J = 6.0 Hz, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 0.8, 7.6 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.55 (dd, J = 0.8, 7.6 Hz, 1H), 9.44 (wide s, 1H).

Elementary analysis: how C21H19N3O3 • HCl • 0.75H2O

C H N calculated 61.31 5.27 10.21 found 61.17 5.04 10.16

Example 8 Hydrochloride 8- [2- (dimethylamino) ethyl] -7H-furo [3,2-c] pyrimido [5,6,1-jk] carbazol-3,7,9 (2H, 8H) -trione

44

They were dissolved in dimethylformamide (20 ml) 590 mg (2.2 mmol) of the compound of Production Example 15. After add 720 mg (4.4 mmol) of N, N'-carbonyldiimidazole, the mixture obtained was stirred at room temperature for 30 minutes. Were added later additionally 0.97 ml (8.8 mmol) of N, N-dimethylethylenediamine and the mixture obtained are stirred overnight followed by concentration. Water was added to residue and the obtained mixture was extracted with an acetate mixture of ethyl with tetrahydrofuran. The organic layer was absorbed, it washed successively with a saturated aqueous bicarbonate solution sodium and water, and dried over magnesium sulfate. After concentrate, the residue was purified by column chromatography of silica gel to give 250 mg of 2,3-dihydro-N- [2- (dimethylamino) ethyl] -3-oxo-6H-furo [3,2-c] carbazol-7-carboxamide.  This product was dissolved in dimethylformamide (10 ml). After add 60 mg (1.5 mmol) of sodium hydride (60% oily), The mixture was stirred under a nitrogen atmosphere for 30 minutes. After adding 0.155 ml (1.5 mmol) of chloroformate ethyl under ice cooling, the obtained mixture was stirred for 30 minutes and then acidified by adding acid to it 1 N hydrochloric. After concentrating, a saturated aqueous sodium bicarbonate solution and the mixture obtained It was extracted with a mixture of ethyl acetate with tetrahydrofuran. The organic layer was absorbed, washed with water, dried over magnesium sulfate, concentrated and purified by chromatography of silica gel column. It was then suspended in ethanol (20 ml). After adding 1 ml of 1 N hydrochloric acid and stirring, recovered crystals by filtration to thereby give 175 ml of title compound.

P.f .: colored from about 240 ° C and decomposed at about 270-273 ° C.

FAB mass spectrometry m / z: 364 ([M + H] +)

\hbox{J =}

7,7 Hz, 1H), 7,95 (d, J = 8,4 Hz, 1H), 8,17 (dd, J = 0,8, 7,7 Hz, 1H), 8,22 (d, J = 8,4 Hz, 1H), 8,43 (dd, J = 0,8, 7,7 Hz, 1H), 9,62 (s ancho, 1H).1H-NMR (DMSO-d6) δ (ppm): 2.89 (broad s, 6H), 3.42-3.50 (m, 2H), 4.39-4.45 (m, 2H), 5.14 (s, 2H), 7.78 (t,

 \ hbox {J =} 

7.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 0.8, 7.7 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 0.8, 7.7 Hz, 1H), 9.62 (wide s, 1H).

Elementary analysis: how C20H17N3O4 • HCl • 0.15H2O

C H N calculated 59.68 4.58 10.44 found 59.64 4.49 10.33

Example 9 2,3-Dihydro-8- [2- (dimethylamino) ethyl] -3-hydroxy-7H-furo [3,2-c] pyrimido [5,6,1-jk] carbazol-7,9 (8H) - diona

Four. Five

They were dissolved in acetic acid (1 ml) 105.5 mg (0.29 mmol) of the compound of Example 8. They were then added to this under stirring at room temperature 36 µl of a complex borane / pyridine 8 M. The mixture obtained was stirred for 4.5 hours. After adding 30 µl of a complex of 8 M borane / pyridine, the mixture obtained was further stirred overnight and concentrated. It was extracted after adding to she water, a saturated aqueous solution of hydrogen carbonate and sodium and chloroform. The organic layer was dried over sodium sulfate anhydrous and concentrated. The residue was purified by chromatography of silica gel column. The product thus obtained was recrystallized. in ethanol / diisopropylether to thereby give 22.6 mg of the compound of the title.

1H-NMR (DMSO-d6) δ (ppm): 2.24 (s, 6H), 2.56 (t, J = 6.8 Hz, 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.56 (dd, J = 2.8, 10.0 Hz, 1H), 4.84 (dd, J = 6.8, 10.0 Hz, 1H), 5.43-5.49 (m, 1H), 5.80 (d, J = 5.6 Hz, 1H), 7.61-7.67 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 0.8, 7.6 Hz, 1H), 8.22 (dd, J = 0.8, 7.6 Hz, 1 HOUR).

Example 10 Hydrochloride 12,13-dihydro-5- [2- (methylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6,10 (5H, 11H) -trione

46

They were dissolved in 20 ml of a mixture of acetonitrile with water (84:16) 0.23 g (0.57 mmol) of the compound of Production example 17 and 95 mg (0.1 mmol) of chloride tris (triphenylphosphine) rhodium (95 mg, 0.1 mmol). Be then heated the mixture obtained under a nitrogen atmosphere to distill the solvent, while adding dropwise to she a mixture of acetonitrile with water (84:16) to keep the Mix volume at a constant level. After continuing this operation for approximately 3 hours, the disappearance of the starting compounds by layer chromatography fine. The reaction mixture was then concentrated until about 1/4 and extracted with ethyl acetate. The layer organic was absorbed, washed successively with aqueous ammonia diluted and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography and later became its hydrochloride by the same method as in Example 4 to give it 0.1 g of the title compound.

P.f .: colored from about 250 ° C, decomposed gradually from about 260 ° C and decomposed quickly at about 267-269 ° C.

FAB mass spectrometry m / z: 362 ([M + H] +)

1H-NMR (DMSO-d6 \ ddD2O) δ (ppm): 2.24-2.34 (m, 2H), 2.59 (s, 3H), 2.76 (wide t, J = 6.0 Hz, 2H), 3.31 (wide t, J = 5.2 Hz, 2H), 3.56 (wide t, J = 6.0 Hz, 2H), 4.36 (wide t, J = 5.2 Hz, 2H), 7.75 (t, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H).

Elementary analysis: how C21H19N3O3 • HCl • 0.2H2O

C H N calculated 62.83 5.12 10.47 found 62.78 5.09 10.36

Example 11 Hydrochloride 12,13-dihydro-5- [2- (1-pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6,10 (5H, 11H) -trione

47

The title compound was obtained by making reacting the compound of Production Example 7 with 1- (2-aminoethyl) pyrrolidine by them methods than those in Production Example 8 and Example 4.

P.f .: colored from about 235 ° C and decomposed gradually from about 260 ° C.

FAB mass spectrometry m / z: 402 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 1.86 (wide s, 2H), 2.01 (wide s, 2H), 2.23-2.32 (m, 2H), 2.71-2.79 (m, 2H), 3.15 (wide s, 2H), 3.46-3.74 (wide t + m, J = 6.0 Hz, 4H + 2H), 4.40 (wide t, J = 5.2 Hz, 2H), 7.73 (t, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 10.10 (wide s, 1H).

Elementary analysis: how C24H23N3O3 • HCl • 1.5H2O

C H N calculated 62.00 5.85 9.04 found 62.27 5.49 9.03

Example 12 Hydrochloride 5- [2- (1-Pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

48

The title compound was obtained by making reacting the compound of Production Example 2 with 1- (2-aminoethyl) pyrrolidine by them methods than those of Production Example 3 and Example 1.

Mass spectrometry FAB m / z: 384 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 1.78-1.92 (m, 2H), 1.94-2.06 (m, 2H), 3.08-3.22 (m, 2H), 3.56 (t, J = 5.6 Hz, 2H), 3.60-3.70 (m, 2H), 4.41 (t, J = 5.6 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.60 (d, J = 9.2 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.98 (d, J = 7.6 Hz, 1H), 10.29 (wide s, 1H).

Elementary analysis: how C24H21N3O3 \ cdotHCl \ cdotH2O

C H N calculated 65.83 5.52 9.60 found 66.04 5.57 9.53

Example 13 Hydrochloride 2- [2- (dimethylamino) ethyl] -5-nitro-1H-benzo [c] pyrimido [5,6,1-jk] phenothiazine-1,3 (2H) -dione

49

A solution of 200 mg (0.49 mmol) of compound of Production Example 23 in tetrahydrofuran (15 ml) it was stirred at room temperature and added successively to it 0.5 ml of triethylamine and 200 µL (2.09 mmol) of chloroformate of ethyl. After stirring at room temperature during night, the reaction mixture was concentrated and extracted by adding to it water, a saturated aqueous solution of hydrogen carbonate and sodium and dichloromethane. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. The residue is recrystallized in ethanol to thereby make 104 mg of the free base of the title compound. Then this product was suspended in methanol and hydrochloric acid was added thereto concentrated. The mixture obtained was then concentrated to dryness. to give for it the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.90 (s, 6H), 3.49 (wide s, 2H), 4.38 (t, J = 5.6 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.49-8.52 (m, 1H), 8.59-8.62 (m, 1H), 9.72 (wide s, 1H).

Example 14 Hydrochloride 2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] thieno [3,2-a] carbazol-1,3 (2H) -dione

fifty

The title compound was obtained from 4-oxo-4,5,6,7-tetrahydro-benzo [b] thiophene and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

\hbox{J
=}

0,8, 7,6 Hz, 1H), 8,84 (d, J = 5,6 Hz, 1H), 9,53 (s ancho, 1H).1H-NMR (DMSO-d6) δ (ppm): 2.92 (broad s, 6H), 3.44-3.57 (m, 2H), 4.44-4.51 (m, 2H), 7.74 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 0.8, 7.6 Hz, 1H ), 8.26 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.65 (dd,

 \ hbox {J
=} 

0.8, 7.6 Hz, 1H), 8.84 (d, J = 5.6 Hz, 1H), 9.53 (wide s, 1H).

Example 15 Hydrochloride 2,3-dihydro-9- [2- (dimethylamino) ethyl] -4H, 8H-pyrano [3,2-c] pyrimido [5,6,1-jk] carbazol-4,8,10 (9H) - triona

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51

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The title compound was obtained by it. procedure as in Example 2.

Mass spectrometry FAB m / z: 378 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.88 (s, 6H), 2.99 (t, J = 6.4 Hz, 2H), 3.46 (s width, 2H), 4.40 (t width, J = 5.6 Hz, 2H), 4.89 (t, J = 6.4 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H), 9.68 (wide s, 1H).

Elementary analysis: how C21H19N3O4 • HCl • 1.25H2O

C H N calculated 57.80 5.20 9.63 found 57.99 5.07 9.69

Example 16 Hydrochloride 9- [2- (dimethylamino) ethyl] -4H, 8H-pyrano [3,2-c] pyrimido [5,6,1-jk] carbazol-4,8,10 (9H) -trione

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52

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The title compound was obtained by it. procedure as in Example 2.

FAB mass spectrometry m / z: 376 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.46 (wide s, 2H), 4.43 (wide t, J = 5.6 Hz, 2H), 6.55 (d, J = 6.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 8.23 (dd, J = 0.8, 7.6 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 6.0 Hz, 1H), 8.65 (dd, J = 0.8, 7.6 Hz, 1H), 9.52 (wide s, 1H).

Example 17 Hydrochloride 2- [2- (dimethylamino) ethyl] -1H-furo [3,2-a] pyrimido [5,6,1-jk] carbazol-1,3 (2H) -dione

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53

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The title compound was obtained from 4-oxo-4,5,6,7-tetrahydrobenzo [b] furan and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.91 (broad s, 6H), 3.40-3.55 (m, 2H), 4.41-4.51 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.61 (d, J = 7.6 Hz, 1H), 9.46 (wide s, 1H).

Example 18 Hydrochloride 2- [2- (dimethylamino) ethyl] -1H-benzo [a] pyrimido [5,6,1-jk] carbazol-1,3 (2H) -dione

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54

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The title compound was obtained from α-tetralone and acid hydrochloride 2-Hydrazinobenzoic and repeating procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.49 (wide s, 2H), 4.49 (t, J = 5.5 Hz, 2H), 7 , 64-7.71 (m, 2H), 7.74 (t, J = 8.0 Hz, 1H), 8.11-8.18 (m, 3H), 8.44 (d, J = 8 , 3 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H), 9.59 (wide s, 1H), 9.76 (d,
J = 8.3 Hz, 1H).

Elementary analysis: how C22H19N3O2 • HCl • 0.2H2O

C H N calculated 66.48 5.17 10.57 found 66.47 5.20 10.51

Example 19 Hydrochloride 5- [3- (dimethylamino) propyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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55

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The title compound was obtained by making reacting the compound of Production Example 2 with N, N-dimethyl-1,3-propanediamine in the same way as in Production Example 3 and Example one.

FAB mass spectrometry m / z: 372 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.03-2.13 (m, 2H), 2.74 (s, 6H), 3.19 (t, J = 8.0 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 8.58 (d, J = 9.6 Hz, 1H), 8.80 (t, J = 8.4 Hz, 1H), 8.94 (d, J = 8.0 Hz, 1H), 9.69 (wide s, 1H).

Elementary analysis: how C23H21N3O2 • HCl • 0.3H2O

C H N calculated 66.84 5.51 10.17 found 66.75 5.45 10.03

Example 20 Hydrochloride 2- [2- (dimethylamino) ethyl] -1H, 11H-indene [1 ', 2': 4,5] pyrrolo [3,2,1-ij] quinazoline-1,3 (2H) -dione

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56

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The title compound was obtained from 2-indanone and acid hydrochloride 2-Hydrazinobenzoic and repeating procedures of Production Examples 1 and 3 and Example 2.

1H-NMR (CD3OD) δ (ppm): 3.02 (s, 6H), 3.53 (t, J = 5.8 Hz, 2H), 4.10 (s, 2H), 4.50 (t, J = 5.8 Hz, 2H), 7.28 (dt, J = 1.2, 7.6 Hz, 1H), 7.41 (dt, J = 1.0, 7.6 Hz, 1H), 7.56-7.59 (m, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.76-7.79 (m, 1H), 8.02 (dd, J = 0.8, 7.7 Hz, 1H), 8.25 (dd, J = 0.8, 7.7 Hz, 1H).

Example 21 Hydrochloride 7- [2- (dimethylamino) ethyl] -6H, 14H-benzo [a] pyrimido [5,6,1-de] acridine-6,8,14 (7H) -trione

57

The title compound was obtained by it. procedure as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.91 (broad s, 6H), 3.50-3.56 (m, 2H), 4.49 (t, J = 5.7 Hz, 2H), 7.64-7.69 (m, 1H), 7.77-7.82 (m, 1H), 7.87-7.92 (m, 1H), 7.98-8.03 (m, 1H), 8.37-8.40 (m, 1H), 8.43-8.46 (m, 1H), 8.63 (dd, J = 0.5, 8.8 Hz, 1H), 9.26 (s, 1H), 9.81 (dd, J = 0.7, 8.6 Hz, 1H), 10.04 (s wide, 1H).

Example 22 Hydrochloride 5- [2- (dimethylamino) ethyl] -11-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

58

The title compound was obtained from 6-methoxy-? -Tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 24 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.93 (d, J = 4.6 Hz, 6H), 3.47-3.54 (m, 2H), 3.94 (s, 3H), 4.39-4.45 (m, 2H), 7.46 (dd, J = 2.2, 9.0 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.59 (d, J = 9.0 Hz, 1H), 8.78 (d, J = 9.0 Hz, 1H), 9.01 (d, J = 8.4 Hz, 1H), 9.16 (wide s, 1H).

Elementary analysis: how C23H21N3O3 • HCl • 1.5H2O

C H N calculated 61.26 5.59 9.32 found 61.08 5.46 9.40

Example 23 Hydrochloride 5- [2- (dimethylamino) ethyl] -10-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

59

The title compound was obtained from 5-methoxy-? -Tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.44-3.51 (m, 2H), 4.04 (s, 3H), 4.40 (t, J = 6.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H), 7.72 (t, J = 8.5 Hz, 1H), 7.73 (dt, J = 3.4, 8.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.52 (dd, J = 1.0, 8.5 Hz, 1H), 8.88 (d, J = 8.5 Hz, 1H), 9.93 (s wide, 1H).

Elementary analysis: how C23H21N3O3 • HCl • 1.3H2O

C H N calculated 61.76 5.54 9.40 found 61.89 5.32 9.45

Example 24 Dihydrochloride 2- [2- (dimethylamino) ethyl] -1H-benzo [b] pyrimido [1,6,5-lm] -4-azacarbazol-1,3 (2H) -dione

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60

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The title compound was obtained by it. procedure as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.90 (s, 6H), 3.47-3.55 (m, 2H), 4.48 (t, J = 6.3 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.86-7.95 (m, 3H), 8.36-8.44 (m, 3H), 9.24-9.29 (m, 1H), 10.41 (wide s, 1H).

Example 25 Hydrochloride 1,2-dihydro-9- [2- (dimethylamino) ethyl] -4H, 8H-pyrano [3,4-c] pyrimido [5,6,1-jk] carbazol-4,8,10 (9H) - triona

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The title compound was obtained by it. procedure as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.47 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 4.38 (t, J = 6.0 Hz, 2H), 4.68 (t, J = 6.0 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 7.6 Hz, 1H), 9.82 (wide s, 1H).

Example 26 Hydrochloride 5- [2- (dimethylamino) ethyl] -12-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

62

The title compound was obtained from 7-methoxy-? -Tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.85 (broad s, 6H), 3.35-3.46 (m, 2H), 4.08 (s, 3H), 4.39 (wide s, 2H), 7.32 (dd, J = 2.2, 8.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 8.09-8.19 (m, 3H), 8.48 (d, J = 8.8 Hz, 1H), 8.97 (d, J = 7.8 Hz, 1H), 9.25 (wide s, 1H).

Example 27 Hydrochloride 2- [2- (dimethylamino) ethyl] -5-nitro-1H-benzo [b] pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) -dione

63

304 mg (1.91 mmol) of 3-amino-2-naphthol, 477 mg (1.81 mmol) of 2-Chloro-3,5-Dinitrobenzate of methyl and 178 mg (2.17 mmol) of sodium acetate in a mixture of water (5 ml) with ethanol (10 ml) and heated under reflux for 7 hours. After adding 3 ml of a 2 N aqueous solution of  sodium hydroxide, the reaction mixture was heated under reflux for an additional 2.5 hours and then returned to room temperature. After adding 10 ml of 1 N hydrochloric acid to it, the precipitate thus formed was recovered by filtration and washed successively with water, 1 N hydrochloric acid and ethanol to give it 430 mg of acid 3-nitro-12H-benzo [b] phenoxazine-1-carboxylic. This product was then treated by the same methods as those of the Production example 23 and Example 13 to thereby give the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.45 (t, J = 5.2 Hz, 2H), 4.40 (t, J = 5.2 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 9.05 (s, 1H), 9.82 (wide s, 1H).

Example 28 Hydrochloride 2-Chloro-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

64

The title compound was obtained from β-tetralone and acid hydrochloride 5-Chloro-2-Hydrazinobenzoic and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (broad s, 6H), 3.39-3.53 (m, 2H), 4.38-4.48 (m, 2H), 7.68-7.75 (m, 1H), 7.81-7.89 (m, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 9.14 (d, J = 1.6 Hz, 1H), 9.46 (wide s, 1H).

Elementary analysis: how C22H18N3O2Cl • HCl • 1.75H2O

C H N calculated 57.46 4.93 9.14 found 57.65 4.57 8.76

Example 29 Hydrochloride 9- [2- (dimethylamino) ethyl] -8H-pyrido [4,3-c] pyrimido [5,6,1-jk] carbazol-1,8,10 (2H, 9H) -trione

65

The title compound was obtained by saponifying an ester of the compound of Production Example 20 and repeating then the procedures of Production Example 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.90 (broad s, 6H), 3.43-3.53 (m, 2H), 4.40-4.46 (m, 2H), 6.80-6.83 (m, 1H), 7.34-7.38 (m, 1H), 7.73 (t, J = 7.9 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 8.18 (dd, J = 0.9, 7.9 Hz, 1H), 8.89 (d, J = 8.9 Hz, 1H), 9.52 (wide s, 1H), 9.91 (dd, J = 0.9, 7.9 Hz, 1H), 11.67-11.71 (m, 1H).

Elementary analysis: how C21H18N4O3 • HCl • 1.3H2O

C H N calculated 58.08 5.01 12.90 found 57.94 4.78 12.72

Example 30 Dihydrochloride 5- [2- (dimethylamino) ethyl] -4H-quino [4 ', 3'-4,5] pyrrolo [3,2,1-ij] quinazoline-4,6 (5H) -dione

66

The title compound was obtained by it. method as in Production Example 2.

FAB mass spectrometry m / z: 359 ([M + H] +)

1H-NMR (DMSO-d6 + D2O) δ (ppm): 2.94 (s, 6H), 3.54 (t width, J = 5.6 Hz, 2H), 4.47 (t width, J = 5.6 Hz, 2H), 7.89 (t, J = 7.6 Hz, 1H), 7.91-7.99 (m, 2H), 8.30-8.37 (m, 2H), 8.89-8.95 (m, 1H), 9.16 (d, J = 7.6 Hz, 1H), 9.97 (s, 1H).

Elementary analysis: how C21H18N4O2 • 2HCl • 0.5H2O

C H N calculated 57.28 4.81 12.72 found 57.28 4.97 12.60

Example 31 Dihydrochloride 5-amino-2- [2- (dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) -dione

67

268 mg (0.641 mmol) of the base was dissolved free of the compound of Example 27 in acetic acid (10 ml) and 10% palladium-carbon was added thereto. It was carried out after catalytic reduction at room temperature in atmosphere of hydrogen After filtering off the palladium-carbon through celite, the filtered out. Then, water and an aqueous solution were added to it. saturated with sodium hydrogen carbonate and the mixture obtained is stirred at room temperature. The precipitate was recovered by filtration, washed with water and suspended in methanol. After add concentrated hydrochloric acid to it, the mixture obtained is stirred at room temperature. Thus, it became a solution homogeneous and then a precipitate formed. The precipitate is recovered by filtration to thereby give 179 mg of the compound of the Title.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.43 (t, J = 5.6 Hz, 2H), 4.34 (t, J = 5.6 Hz, 2H), 6.76 (s, 1H), 6.96 (s, 1H), 7.38-7.48 (m, 2H), 7.59 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 9.15 (s, 1H), 9.65 (wide s, 1H).

Example 32 Hydrochloride 5- [2- (dimethylamino) ethyl] -13-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

68

The title compound was obtained from 8-methoxy-? -Tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

\hbox{J =}

7,6 Hz, 1H), 7,61 (t, J = 8,0 Hz, 1H), 7,72-7,79 (m, 2H), 8,15 (d, J = 8,0 Hz, 1H), 8,23 (d, J = 8,8 Hz, 1H), 8,82 (d, J = 8,8 Hz, 1H), 9,09 (d, J = 8,0 Hz, 1H), 9,35 (s ancho, 1H).1H-NMR (DMSO-d6) δ (ppm): 2.91 (wide s, 6H), 3.40-3.53 (m, 2H), 4.23 (s, 3H), 4.40- 4.49 (m, 2H), 7.33 (d,

 \ hbox {J =} 

7.6 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.72-7.79 (m, 2H), 8.15 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.82 (d, J = 8.8 Hz, 1H), 9.09 (d, J = 8.0 Hz, 1H) , 9.35 (wide s, 1H).

Elementary analysis: how C23H21N3O3 • HCl • 0.65H2O

C H N calculated 63.42 5.39 9.65 found 63.31 5.14 9.68

Example 33 Dihydrochloride 9- [2- (dimethylamino) ethyl] -8H-pyrido [4,3-c] pyrimido [5,6,1-jk] carbazol-8,10 (9H) -dione

69

300 mg (1.1 mmol) of the compound was dissolved of Production Example 21 in a mixture of tetrahydrofuran (10 ml) with methanol (10 ml). After adding 5 ml of hydroxide to it 1N sodium, the obtained mixture was heated under reflux for 1 hour. It then dissolved acid 7H-pyrido [4,3-c] carbazol-8-carboxylic acid, conventionally isolated, in dimethylformamide (40 ml) and added 360 mg (2.2 mmol) of N, N'-carbonyldiimidazole. After stirring to room temperature for 30 minutes, 0.48 was added thereto ml (4.4 mmol) of N, N-dimethylethylenediamine and the obtained mixture was stirred overnight. After concentrating, It was extracted by adding water and ethyl acetate. The organic layer is absorbed, washed successively with a saturated aqueous solution of sodium bicarbonate and water, and dried over magnesium sulfate. After concentrating, the residue was purified by chromatography of silica gel column to give 250 mg of N- [2- (dimethylamino) ethyl] -7H-pyrido [4,3-c] carbazol-8-carboxamide. Afterwards, this product was reacted and treated in the same way than that of Example 2 to thereby give 110 mg of the compound of Title.

P.f .: colored from about 270 ° C and decomposed at 279 ° C.

1H-NMR (DMSO-d6) δ (ppm): 2.89-2.93 (m, 6H), 3.49-3.54 (m, 2H), 4.46 (t, J = 6.0 Hz, 2H), 7.85 (t, J = 7.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.40-8.44 (m, 2H), 8.79 (d, J = 6.4 Hz, 1H), 9.04 (d, J = 9.2 Hz, 1H), 9.23 (d, J = 7.6 Hz, 1H), 10.10 (wide s, 1H), 10.44 (s, 1 H).

Elementary Analysis: C21H18N4O2 \ cdot2HCl \ cdot2H2O

C H N calculated 53.97 5.18 11.99 found 54.11 4.99 11.99

Example 34 Hydrochloride 5- [4- (dimethylamino) butyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

70

The title compound was obtained by making reacting the compound of Production Example 2 with N, N-dimethyl-1,4-butanediamine by the same methods as in Production Example 3 and the Example 1.

Mass spectrometry FAB m / z: 386 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 1.68-1.85 (m, 4H), 2.74 (s, 6H), 3.09 (wide t, J = 6.4 Hz, 2H), 4.10 (wide t, J = 6.4 Hz, 2H), 7.64-7.70 (m, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.79-7.85 (m, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.16-8.24 (m, 2H), 8.62 (d, J = 8.8 Hz, 1H), 8.83 (d, J = 8.4 Hz, 1H), 8.97 (d, J = 7.6 Hz, 1H), 9.99 (wide s, 1 HOUR).

Elementary analysis: how C24H23N3O2 • HCl • 0.5H2O

C H N calculated 66.89 5.85 9.75 found 66.54 5.71 9.66

Example 35 Hydrochloride 11-cyano-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

71

The title compound was obtained from it. so as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.93 (s, 6H), 3.48-3.55 (m, 2H), 4.46 (t, J = 5.6 Hz, 2H), 7.83 (t, J = 8.2 Hz, 1H), 8.10 (dd, J = 1.3, 8.9 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.79 (d, J = 8.9 Hz, 1H), 8.88 (d, J = 1.3 Hz, 1H), 9.04 (d, J = 8.9 Hz, 1H), 9.10 (d, J = 8.2 Hz, 1H).

Example 36 Dihydrochloride 9- [2- (dimethylamino) ethyl] -8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazol-8,10 (9H) -dione

72

The title compound was obtained from it. so as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.92 (s, 6H), 2.93 (s, 3H), 3.46-3.58 (m, 2H), 4.41-4.51 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H), 7.92 (dd, J = 4.8, 8.4 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.92 (d, J = 9.2 Hz, 1H), 9.10 (d, J = 8.0 Hz, 1H), 9.14 (dd, J = 0.8, 4.8 Hz, 1H), 9.47 (dd, J = 0.8, 8.4 Hz, 1H), 9.86 (wide s, 1H).

Elementary analysis: how C21H18N4O2 • 2HCl • 0.75H2O

C H N calculated 56.70 4.87 12.59 found 56.78 4.82 12.36

Example 37 Hydrochloride 5- [2- (dimethylamino) ethyl] -2-nitro-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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The title compound was obtained from β-tetralone and acid 5-nitro-2-hydrazinobenzoic and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (s, 6H), 3.44-3.52 (m, 2H), 4.45 (t, J = 5.2 Hz, 2H), 7.73 (t, J = 8.1 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.63 (d, J = 9.2 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 8.1 Hz, 1H), 9.64 (d, J = 1.8 Hz, 1H), 9.75 (wide s, 1H).

Example 38 Hydrochloride 5- [2- (dimethylamino) ethyl] -2-methyl-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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The title compound was obtained from β-tetralone and acid hydrochloride 2-hydrazino-5-methylbenzoic and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.71 (s, 3H), 2.90 (wide s, 6H), 3.38-3.55 (m, 2H), 4.39-4.46 (m, 2H), 7.66-7.72 (m, 1H), 7.81-7.88 (m, 1H), 7.97-8.00 (m, 1H), 8.18-8.23 (m, 1H), 8.22-8.27 (m, 1H), 8.63 (d, J = 9.2 Hz, 1H), 8.88-8.95 (m, 2H).

Elementary analysis: how C23H21N3O2 • HCl • 1.5H2O

C H N calculated 63.52 5.79 9.66 found 63.63 5.48 9.70

Example 39 Hydrochloride 1,2-dihydro-9- [2- (dimethylamino) ethyl] -8H-pyrido [3,4-c] pyrimido [5,6,1-jk] carbazol-4,8,10 (3H, 9H) - triona

75

The title compound was obtained from it. so as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.88 (broad s, 6H), 3.37-3.52 (m, 2H), 3.50-3.64 (m, 4H), 4.36-4.44 (m, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.11 (wide s, 1H), 8.15 (dd, J = 0.8, 7.6 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.57 (dd, J = 0.8, 7.6 Hz, 1H).

Elementary analysis: how C21H20N4O3 \ cdotHCl \ cdotH2O

C H N calculated 58.54 5.38 13.00 found 58.50 5.49 12.77

Example 40 Hydrochloride 8- [2- (dimethylamino) ethyl] -7H-1,3-dioxolo [4,5-c] pyrimido [5,6,1-jk] carbazol-7,9 (8H) -dione

76

The title compound was obtained from it. so as in Example 2.

\hbox{J =}

8,4 Hz, 1H), 7,68 (t, J = 7,7 Hz, 1H), 7,89 (d, J = 8,4 Hz, 1H), 8,10 (dd, J = 0,8, 7,7 Hz, 1H), 8,27 (dd, J = 0,8, 7,7 Hz, 1H), 9,35 (s ancho, 1H).1H-NMR (DMSO-d6) δ (ppm): 2.90 (broad s, 6H), 3.42-3.49 (m, 2H), 4.36-4.42 (m, 2H), 6.35 (s, 2H), 7.29 (d,

 \ hbox {J =} 

8.4 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 0, 8, 7.7 Hz, 1H), 8.27 (dd, J = 0.8, 7.7 Hz, 1H), 9.35 (wide s, 1H).

Example 41 Hydrochloride 11-Bromo-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

77

The title compound was obtained from 6-bromo-? -Tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

FAB m / z mass spectrometry: 436 ([M + H] +), 438 ([M + 2 + H] +),

1H-NMR (DMSO-d6) δ (ppm): 2.90 (s, 3H), 3.48 (wide s, 2H), 4.42 (t, J = 5.6 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.79 (d, J = 9.2 Hz, 1H), 8.97 (d, J = 8.0 Hz, 1H), 9.74 (wide s, 1H).

Elementary analysis: how C22H18N3O2Br \ HCl \ 0.6H2O

C H N calculated 54.64 4.21 8.69 found 54.36 3.94 8.56

Example 42 Hydrochloride 2- [2- (dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-jk] carbazol-1,3 (2H) -dione

78

The title compound was obtained from it. so as in Example 2.

FAB mass spectrometry m / z: 358 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.90 (broad s, 6H), 3.39-3.53 (m, 2H), 4.37-4.48 (m, 2H), 7.60-7.70 (m, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.13 (dd, J = 0.8, 7.6 Hz, 1H), 8.16-8.20 (m, 1H), 8.21-8.26 (m, 1H), 8.66 (dd, J = 0.8, 7.6 Hz, 1H), 8.86 (s, 1H), 8.93 (s, 1 HOUR).

Elemental analysis: as C22H19N3O2 \ cdotHCl

C H N calculated 67.09 5.12 10.67 found 66.94 5.22 10.65

Example 43 Hydrochloride 5- [2- (dimethylamino) ethyl] -10,11,12,13-tetrahydro-4H-benzo [b] pyrimido [5,6,1-jk] carbazol-4,6 (5H) - diona

79

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The title compound was obtained from compound of Example 4 in the same manner as that of Example 5.

FAB mass spectrometry m / z: 362 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 1.79-2.01 (m, 4H), 2.89 (s, 6H), 2.90 (wide t, J = 6.0 Hz, 2H), 3.24 (wide t, J = 6.0 Hz, 2H), 3.46 (wide t, J = 5.6 Hz, 2H), 4.39 (wide t, J = 6.0 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.41 (dd, J = 0.8, 8.0 Hz, 1H), 9.74 (wide s, 1H).

Elementary analysis: how C22H23N3O2 • HCl • 0.75H2O

C H N calculated 64.23 6.25 10.21 found 64.35 6.20 10.15

Example 44 Hydrochloride 12,13-dihydro-11,11-dimethyl-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6,10 (5H, 11H ) -trione

80

The title compound was obtained from it. so as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 1.20 (s, 6H), 2.13 (t, J = 6.1 Hz, 2H), 2.88 (s, 6H), 3.43 (wide s, 2H), 3.52 (t, J = 6.1 Hz, 2H), 4.38 (t, J = 5.7 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 7.4 Hz, 1H), 10.08 (wide s, 1H).

Elementary analysis: how C24H25N3O3 \ cdotHCl \ cdotH2O

C H N calculated 62.94 6.16 9.18 found 63.06 6.27 9.14

Example 45 Hydrochloride 5- [2- (dimethylamino) ethyl] -2-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

81

The title compound was obtained from β-tetralone and acid hydrochloride 2-hydrazino-5-methoxybenzoic and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

FAB m / z mass spectrometry: 436 ([M + H] +), 438 ([M + 2 + H] +),

1H-NMR (DMSO-d6) δ (ppm): 2.89 (broad s, 6H), 3.40-3.52 (m, 2H), 4.03 (s, 3H), 4.40 (t, J = 6.0 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.63-7.70 (m, 1H), 7.76-7.85 (m, 1H), 8.17 (dd, J = 0.4, 8.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.84 (dd, J = 0.4, 8.4 Hz, 1H), 9.57 (wide s, 1H).

Elementary analysis: how C23H21N3O3 \ cdotHCl \ cdotH2O

C H N calculated 62.51 5.47 9.51 found 62.44 5.22 9.48

Example 46 Hydrochloride 5- [2- (dimethylamino) ethyl] -11-hydroxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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82

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The compound of Example 22 was heated under 47% hydrobromic acid reflux. It was reduced catalytically then the reaction mixture at room temperature by means of the use of palladium-carbon as a catalyst. The product  obtained was converted into the hydrochloride by a conventional method to give for it the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.92 (d, J = 5.5 Hz, 6H), 3.48 (q, J = 5.5 Hz, 2H), 4.41 (t, J = 5.5 Hz, 2H), 7.36-7.42 (m, 2H), 7.73 (t, J = 8.1 Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.71 (d, J = 9.4 Hz, 1H), 8.94 (d, J = 8.1 Hz, 1H), 9.60 (wide s, 1H), 10.01 (wide s, 1H).

Example 47 Dihydrochloride 5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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83

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The compound of Example 37 was hydrogenated in presence of a palladium-carbon catalyst at ordinary temperature under atmospheric pressure to give the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (d, J = 4.1 Hz, 6H), 3.44-3.51 (m, 2H), 4.40 (t, J = 5.8 Hz, 2H), 7.67 (t, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.84 (t, J = 8.2 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 9.3 Hz, 1H), 8.57 (d, J = 9.3 Hz, 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.63 (s, 1H), 9.94 (wide s, 1H).

Example 48 Hydrochloride 5- [2- (dimethylamino) ethyl] -11- (4-methylbenzenesulfonamido) -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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84

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The compound of Production Example 24 is treated in the same way as in Production Example 3 to give thus N- [2- (dimethylamino) ethyl] -3- (4-methylbenzenesulfonamido) -7H-benzo [c] carbazol-8-carboxamide. This product was then reacted with sodium hydride and ethyl chloroformate in dimethylformamide under cooling with ice to give for it 5- [2- (dimethylamino) ethyl] -11- (N-ethoxycarbonyl-4-methylbenzenesulfonamido) -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione. This product was then treated with a 1 N aqueous solution. of sodium hydroxide in a mixture of methanol with tetrahydrofuran (1: 1) and then converted to hydrochloride so conventional followed by recrystallization in ethanol to give that is the title compound.

1H-NMR (DMSO-d6) δ (ppm): 2.28 (s, 3H), 2.90 (s, 6H), 3.48 (wide s, 2H), 4.41 (t, J = 5.6 Hz, 2H), 7.33 (d, J = 9.2 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.70-7.78 (m, 3H), 7.82 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 9.56 (s width, 1H), 10.68 (s, 1H).

Example 49 Dihydrochloride 11-amino-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

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85

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They were heated under reflux in hydrobromic acid 47% (15 ml) 341 mg (0.648 mmol) of the free base of the compound of Example 48 and 419 mg (4.45 mmol) of phenol, for 9 hours and 30 minutes, and then returned to room temperature. Mix reaction was done after basic adding to it a solution saturated aqueous sodium hydrogen carbonate. Then, the mixture obtained was extracted by adding ethyl acetate and tetrahydrofuran. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated and the residue obtained was recrystallized from ethanol to thereby give 141 mg. of the free base of the title compound. Became later this free base in the hydrochloride in a conventional way to give hence the title compound.

(free base) 1H-NMR (DMSO-d6) δ (ppm): 2.22 (s, 6H), 2.55 (t, J = 6.8 Hz, 2H), 4.14 (t, J = 6.8 Hz, 2H), 5.50-5.53 (m, 2H), 7.06 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 2.4, 9.2 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.84 (d, J = 7.6 Hz, 1H).

Example 50 Hydrochloride 11-acetamido-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

86

4 ml of triethylamine were successively added and 2 ml acetic anhydride to a suspension of 141 mg (0.379 mmol) of the free base of the compound of Example 49 in dichloromethane (20 ml) under stirring at room temperature, and the stirring for 16 hours. After concentrating, they were added to the 30 ml residue of methanol. Next, the mixing became basic obtained by adding an aqueous carbonate solution of hydrogen and sodium The precipitate was recovered by filtration and was washed with water. The solid matter thus obtained was suspended in ethanol and concentrated hydrochloric acid under it was added stirring at room temperature. After adding additionally to it methanol and dichloromethane, stirring was continued. After if concentrated, ethanol was added thereto and the mixture obtained was heated under reflux and then returned to room temperature. He precipitate was recovered by filtration to thereby give 148 mg of title compound.

FAB mass spectrometry m / z: 415 ([M + H] +)

1H-NMR (DMSO-d6) δ (ppm): 2.13 (s, 3H), 2.90 (s, 3H), 2.91 (s, 3H), 3.44-3.52 (m, 2H), 4.42 (t, J = 5.6 Hz, 2H), 7.76 (t, J = 8.0 Hz, 1H), 7.89 (dd, J = 1.6, 9.2 Hz, 1H), 8.06-8.14 (m, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.54 (d, J = 9.2 Hz, 1H), 8.79 (d, J = 8.8 Hz, 1H), 8.98 (d, J = 8.0 Hz, 1H), 9.60 (wide s, 1H), 10.35 (s, 1H).

Elementary analysis: how C24H22N4O3 \ HCl \ 0.6H2O

C H N calculated 62.43 5.28 12.13 found 62.54 5.03 11.82

Example 51 Dihydrochloride 5- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -diona

87

The title compound was obtained from it. so as in Example 2.

(free base) 1H-NMR (CDCl3) δ (ppm): 2.20 (s, 6H), 2.42 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.63 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 4.35 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.56-8.61 (m, 2H), 8.66 (d, J = 9.2 Hz, 1H).

Elementary analysis: how C25H26N4O2 • 2HCl • 0.8H2O

C H N calculated 59.83 5.78 11.17 found 59.83 6.02 11.16

Example 52 Hydrochloride 5- [2- [N- [2- (hydroxyethyl) -N-methylamino] ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

88

The title compound was obtained from it. so as in Example 2.

1H-NMR (DMSO-d6) δ (ppm): 2.93 (s, 3H), 3.14-3.67 (m, 4H), 3.71-3.80 (m, 2H), 4.40-4.49 (m, 2H), 5.33-5.39 (m, 1H), 7.64-7.70 (m, 1H), 7.73-7.86 (m, 2H), 8.10-8.26 (m, 3H), 8.59-8.65 (m, 1H), 8.83-8.89 (m, 1H), 9.00-9.04 (m, 1H), 9.60 (wide s, 1H).

Elementary analysis: how C23H21N3O3 • HCl • 1.1H2O

C H N calculated 62.26 5.25 9.47 found 62.08 5.55 9.47

Example 53 Hydrochloride 5- [2- (dimethylamino) ethyl] -2-hydroxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazol-4,6 (5H) -dione

89

The title compound was obtained by treating the compound of Example 45 in the same manner as in Example 46.

1H-NMR (DMSO-d6) δ (ppm): 2.89 (broad s, 6H), 3.39-3.54 (m, 2H), 4.32-4.46 (m, 2H), 7.53-7.56 (m, 1H), 7.65-7.71 (m, 1H), 7.81-7.87 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.35-8.39 (m, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.73 (d, J = 8.0 Hz, 1H), 9.29-9.39 (width, 1H), 10.25 (s, 1H).

Elementary analysis: how C22H19N3O3 \ cdotHCl \ cdotH2O

C H N calculated 61.76 5.18 9.82 found 61.92 4.90 9.84

Example 54 Hydrochloride 2- [2- (dimethylamino) ethyl] -9-methoxy-1H-benzo [a] pyrimido [5,6,1-jk] carbazol-1,3 (2H) -dione

90

The title compound was obtained from 5-methoxy-1-tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedure of Example 18.

1H-NMR (DMSO-d6) δ (ppm): 2.92 (s, 6H), 3.46-3.55 (m, 2H), 4.02 (s, 3H), 4.42-4.46 (m, 2H), 7.16 (d, J = 7.1 Hz, 1H), 7.60 (t, J = 7.1 Hz, 1H), 7.73 (t, J = 7.1 Hz, 1H), 8.12 (d, J = 7.1 Hz, 1H), 8.34-8.44 (m, 2H), 8.63 (d, J = 7.1 Hz, 1H), 9.28 (d, J = 9.2 Hz, 1H), 9.78 (wide s, 1H).

Example 55 Dihydrochloride 9- [2- (1-Pyrrolidinyl) ethyl] -8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazol-8,10 (9H) -dione

91

The title compound was obtained from it. so as in Example 36.

1H-NMR (DMSO-d6 + D2O) δ (ppm): 1.84-1.94 (m, 2H), 2.01-2.13 (m, 2H), 3.13-3.25 (m, 2H), 3.57-3.64 (m, 2H), 3.65-3.74 (m, 2H), 4.43-4.49 (m, 2H), 7.85 (t, J = 7.6 Hz, 1H), 7.94 (dd, J = 4.4, 8.4 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.92 (d, J = 9.2 Hz, 1H), 9.05 (d, J = 7.6 Hz, 1H), 9.12 (dd, J = 1.6, 4.4 Hz, 1H), 9.40-9.45 (m, 1 HOUR).

Example 56 Dihydrochloride 9- [2- (dimethylaminol) ethyl] -13-fluoro-8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazol-8,10 (9H) -dione

92

The title compound was obtained from it. so as in Example 36.

\hbox{J =}

8,4, 12,0 Hz, 1H), 7,93 (dd, J = 4,4, 8,4 Hz, 1H), 8,29 (dd, J = 4,4, 8,4 Hz, 1H), 8,45 (d, J = 9,2 Hz, 1H), 8,97 (d,

\hbox{J =}

9,2 Hz, 1H), 9,10-9,14 (m, 1H), 9,25-9,31 (m, 1H).1H-NMR (DMSO-d6 + D2O) δ (ppm): 2.92 (s, 3H), 2.93 (s, 3H), 3.47-3.55 (m, 2H), 4.41 -4.47 (m, 2H), 7.69 (dd,

 \ hbox {J =} 

8.4, 12.0 Hz, 1H), 7.93 (dd, J = 4.4, 8.4 Hz, 1H), 8.29 (dd, J = 4.4, 8.4 Hz, 1H ), 8.45 (d, J = 9.2 Hz, 1H), 8.97 (d,

 \ hbox {J =} 

9.2 Hz, 1H), 9.10-9.14 (m, 1H), 9.25-9.31 (m, 1H).

Example 57 Dihydrochloride 9- [2- (dimethylaminol) ethyl] -3-methyl-8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazol-8,10 (9H) -dione

93

The title compound was obtained from it. so as in Example 36.

1H-NMR (DMSO-d6 + D2O) δ (ppm): 2.93 (s, 3H), 2.95 (s, 6H), 3.51-3.57 (m, 2H), 4.44-4.50 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 8.98 (d, J = 9.2 Hz, 1H), 9.09 (d, J = 8.0 Hz, 1H), 9.55 (d, J = 8.8 Hz, 1H).

Example 58 7- [2- (Dimethylaminol) ethyl] -6H-benzo [c, i] pyrimido [1,6,5-lm] -? -Carboline-6,8 (7H) -dione

94

1.06 g (3.1 mmol) of the compound was dissolved of Production Example 25 in a mixture of methanol (20 ml) with tetrahydrofuran (20 ml). After adding a solution to it 1 N aqueous sodium hydroxide (10 ml), the mixture obtained is heated under reflux for 1 hour and then allowed to cool. Next, a 1 N aqueous solution of acid was added thereto. hydrochloric (10 ml) and the solvent was distilled off. Was added to N, N-dimethylformamide residue (50 ml). Additionally, 770 mg (4 mmol) of hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 540 mg (4 mmol) of 1-hydroxybenzotriazole and 0.4 ml (3.7 mmol) of N, N-dimethylethylenediamine, and the obtained mixture was stirred at room temperature overnight. Be then added to it an aqueous solution of hydrogen carbonate and sodium and the mixture was extracted with ethyl acetate. The layer organic was washed with water and a saturated aqueous solution of chloride Sodium, dried over anhydrous magnesium sulfate and concentrated after. The precipitate thus formed was washed with ethanol and recovered by filtration to thereby give 660 mg of a compound intermediate (yield: 55%).

100 mg (0.26 mmol) of this was dissolved intermediate compound in N, N-dimethylformamide (20 ml) and were added thereto under a stream of nitrogen gas 22 mg (0.55 mmol) of sodium hydride (60% oily). After stir the obtained mixture for 1 hour, they were added to ambient temperature 0.046 ml (0.6 mmol) of chloroformate methyl. Then, the mixture was immediately acidified with acid 1 N hydrochloric and then became weakly alkaline with a saturated aqueous sodium hydrogen carbonate solution followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated to dryness. He residue was purified by silica gel column chromatography to thereby give 25 mg of the title compound (yield: 24%)

FAB mass spectrometry m / z: 409 ([M + H] +)

1H-NMR (CDCl3) δ (ppm): 2.39 (s, 6H), 2.80 (t, J = 6.7 Hz, 2H), 4.51 (t, J = 6.7 Hz, 2H), 7.66-7.78 (m, 2H), 7.85-7.93 (m, 2H), 8.01-8.07 (m, 2H), 8.51 (d, J = 8.6 Hz, 1H), 8.57-8.63 (m, 1H), 8.73-8.79 (m, 1H), 9.74 (dd, J = 0.7, 8.6 Hz, 1H).

Claims (13)

1. A compound represented by the following general formula (I) or acceptable salts thereof pharmacologically: 95 in the that ring A represents an aromatic ring optionally substituted monocyclic or a condensed ring bicyclic in which at least one of the rings is a ring aromatic; ring B represents pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone; ring C represents an aromatic ring monocyclic or bicyclic condensate, optionally substituted; and And represents a represented group or formula -e-f (in which e represents an alkylene C1-C6 and f represents amidino, guanidino or amino optionally substituted with C1-C6 alkyl optionally hydroxylated or optionally C1-C6alkylated alkyl; on the condition that cases in which rings A and C are both monocyclic aromatic rings optionally substituted, in which optionally substituted in the case of ring A means 1 to 3 substituents selected from the group consisting of hydroxy, oxo, cyano, halogen, nitro optionally hydroxylated or C1-C6 alkyl optionally C1-C6 alkyl, alkoxy C1-C6, acyl C1-C6, carbamoyl optionally C1-C6 alkylated and amino optionally C1-C6 alkylated, C1-C6 acylated, arylsulfonylated or C1-C6 alkyl sulfonylated, and in the which optionally substituted in the case of ring C means 1 to 3 substituents selected from the groups consisting of include halogen, hydroxy, C1-C6 alkyl, alkoxy C1-C6, nitro and C1-C6 amino alkylated or C1-C6 acylated. 2. The compound as indicated in the claim 1, wherein ring A is a naphthalene, indene, benzocycloheptene or benzocyclooctene which is optionally substituted and optionally hydrogenated in a ring, or salts of the same pharmacologically acceptable. 3. The compound as indicated in the claim 1, wherein ring A is a quinoline, isoquinoline, 4H-1-benzopyran, 1H-2-benzopyran, 1,3-benzodioxol, benzofuran, isobenzofuran, benzothiophene, indole or isoindole which is optionally substituted and optionally hydrogenated in a ring and condensed with ring B in the rest of the benzene ring thereof, or salts thereof pharmacologically acceptable. 4. The compound as indicated in the claim 1, wherein ring A is a tetralin or indane optionally substituted and condensed with ring B in the rest benzene ring thereof, or acceptable salts thereof pharmacologically 5. The compound as indicated in the claim 1, wherein ring A is a tetralin or indane oxo-substituted and condensed with ring B in the benzene ring moiety thereof, or acceptable salts thereof pharmacologically 6. The compound as indicated in the claim 1, wherein ring A is a chromane, isochroman, tetrahydrobenzofuran or tetrahydroisobenzofuran optionally replaced and condensed with ring B in the rest of the ring benzene thereof, or acceptable salts thereof pharmacologically 7. The compound as indicated in the claim 1, wherein ring B is a pyrrole, or salts of the same pharmacologically acceptable. 8. The compound as indicated in the claim 1, wherein the ring C is a benzene optionally substituted, or acceptable salts thereof pharmacologically 9. The compound according to any of the claims 1 to 8, wherein f in the definition of Y is a amino substituted with C1-6 alkyl, or salts thereof  pharmacologically acceptable. 10. A process for producing a compound as indicated in claim 1, or pharmacologically acceptable salts thereof, characterized by reacting a compound represented by the following general formula (II): 96 in which the rings Aa and Ca respectively represent rings A and C optionally protected as described in claim 1; the Ba ring represents a pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone; fa represents an f optionally protected as described in the claim 1st; and e has the same meaning defined in the claim 1st, with a compound represented by the following general formula (III): (III) D ---

 \ delm {C} {\ delm {\ dpara} {O}} 

---AND in which D and E are equal or different and each represents a labile group, and eliminate the protective group (s), if any, of the product obtained So. 11. An anti-tumor agent that contains as active ingredient a polycyclic heterocycle derivative condensate according to any one of claims 1 to 9, or salts thereof pharmacologically acceptable. 12. A medicinal composition comprising a pharmacologically effective dose of the heterocycle derivative condensed polycyclic according to any of claims 1 to 9th, or pharmacologically acceptable salts thereof, and excipients pharmacologically acceptable. 13. The use of a compound according to any of the claims 1 to 9, or acceptable salts thereof pharmacologically, in a pharmacologically effective dose for manufacture of a medicinal composition to prevent or treat tumors